Compounds and methods for kinase modulation, and indications therefor

ABSTRACT

Compounds active on protein kinases are described, as well as methods of making and using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

FIELD OF THE INVENTION

The present invention relates to kinases and compounds which selectivelymodulate kinases, and uses therefor. Particular embodiments contemplatedisease indications which are amenable to treatment by modulation ofkinase activity by the compounds of the present invention.

BACKGROUND OF THE INVENTION

Receptor protein kinases regulate key signal transduction cascades thatcontrol or are involved in the control of a plethora of physiologicalfunctions including cellular growth and proliferation, celldifferentiation, cellular development, cell division, cell adhesion,stress response, short-range contact-mediated axonal guidance,transcription regulation, aberrant mitogenesis, angiogenesis, abnormalendothelial cell-cell or cell-matrix interactions during vasculardevelopment, inflammation, lymphohematopoietic stem cell activity,protective immunity against specific bacteria, allergic asthma, aberranttissue-specific responses to the activation of the JNK signaltransduction pathway, cell transformation, memory, apoptosis,competitive activity-dependent synapse modification at the neuromuscularsynapse, immunological mediation of disease, and calcium regulation.

Specific disease states associated with aberrant regulation of proteinkinases include, for example without limitation, acrocephalo-syndactylytype I, acute myeloid leukemia, AIDS-induced non-Hodgkin's lymphoma,Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma,atherosclerosis, atopic dermatitis, autoimmune diseases, bacterialinfection, bladder cancer, cancer of the breast, cancer of the centralnervous system, cancer of the colon, cancer of the endometrium, cancerof the fallopian tube, cancer of the gastrointestinal tract, cancer ofthe ovary, heart failure, chronic myeloid leukemia, colon carcinoma,colorectal cancer, chronic obstructive pulmonary disease (COPD), CrouzonSyndrome, diabetes, diabetic nephropathy, emphysema, endometriosis,epidermoid cancer, fibrotic disorders, gastrointestinal stromal tumor(GIST), glomerulonephritis, Graves' disease, head injury, hepatocellularcarcinoma, Hirschsprung's disease, human gliomas, immunodeficiencydiseases, inflammatory disorders, ischemic stroke, Jackson-Weisssyndrome, leiomyosarcoma, leukemias, lupus nephritis, malignantmelanoma, malignant nephrosclerosis, mastocytosis, mast cell tumors,melanoma of the colon, MEN2 syndromes, metabolic disorders, migraine,multiple sclerosis, myeloproliferative disorders, nephritis,neurodegenerative diseases, neurotraumatic diseases, non small cell lungcancer, organ transplant rejection, osteoporosis, pain, Parkinson'sdisease, Pfeiffer Syndrome, polycystic kidney disease, primarylymphoedema, prostate cancer, psoriasis, vascular restenosis, rheumatoidarthritis, dermal and tissue scarring, selective T-cell defect (STD),severe combined immunodeficiency (SCID), small cell lung cancer, spinalcord injury, squamous cell carcinoma, systemic lupus erythematosis,testicular cancer, thrombotic microangiopathy syndromes, Wegener'sgranulomatosis, X-linked agammaglobulinemia, viral infection, diabeticretinopathy, alopecia, erectile dysfunction, macular degeneration,chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS),neurofibromatosis, and tuberous sclerosis. Accordingly, there is a needin the art for compounds and methods of use thereof for the modulationof receptor protein kinases. The present invention meets this and otherneeds.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula I:

and pharmaceutically acceptable salts, hydrates, solvates, tautomers andisomers thereof, wherein:

Y¹ is selected from the group consisting of CN, halogen, —OH, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, optionallysubstituted C₃₋₆cycloalkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ haloalkoxy, optionally substituted aryl andoptionally substituted heteroaryl; optionally wherein two adjacentsubstituents on a substituted aryl or a substituted heteroaryl ringtogether with the atoms to which they are attached form an optionallysubstituted 5- or 6-membered ring having from 0 to 3 additionalheteroatoms selected from N, O or S;

Y² is H, halogen, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C₃₋₈cycloalkyl-C₀₋₄ alkyl or (R²)(R³)N—, wherein R² and R³ are eachindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C₃₋₈cycloalkyl-C₀₋₄ alkyl, heterocycloalkyl and heterocycloalkyl-C₁₋₄ alkyl;or R² and R³ taken together with the nitrogen atom to which they areattached form a three to eight-membered ring having from 0-2 additionalheteroatoms as ring members selected from N, O or S; wherein Y² isoptionally substituted with from one to three groups independentlyselected from R^(e);

Q is selected from H, F, Cl or CH₃;

Z is —N(R⁴)(R⁵) or —C(R⁶)(R⁷)(R⁸), wherein

R⁴ and R⁵ are each independently selected from the group consisting ofH, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₃₋₈ cycloalkylalkyl, optionallysubstituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl; or R⁴ and R⁵ taken together with thenitrogen atom to which they are attached form a four to eight-memberedring having from 0-2 additional heteroatoms as ring members selectedfrom N, O or S, wherein the four to eight-membered ring is optionallysubstituted;

R⁶, R⁷ and R⁸ are each independently H, optionally substituted C₁₋₆alkyl, optionally substituted, C₁₋₆ haloalkyl, optionally substitutedC₁₋₆ haloalkoxy, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₃₋₈ cycloalkylalkyl, optionally substituted aryl,optionally substituted arylalkyl, optionally substitutedheterocycloalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl or —X²R⁹, wherein X² is —NR¹⁰, O or S; R¹⁰ is H, C₁₋₆alkyl or aryl; and R⁹ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, wherein R⁹ is optionally substituted with from 1 to 3R^(e) substituents; or

any two of the R⁶, R⁷ and R⁸ groups taken together with the carbon atomto which they are attached form a 3 to 8-membered optionally substitutednon-aromatic ring having from 0 to 2 heteroatoms selected from N, O orS; provided at each occurrence, at least two of the R⁶, R⁷ and R⁸ groupsare not simultaneously hydrogen; and with the proviso when (i) Y¹ ishalogen, —CH₃, —CN, —OMe or 2-methoxypyrimidin-5-yl, Z is other thandimethylamino, diethylamino, 1-pyrrolidine, 1-piperidinyl,4-morpholinyl, isopropyl, —CH(CH₃)(CH₂CH₃), —CH(CH₃)(CH₂CH₂CH₃),cyclobutyl, cyclopentyl or cyclohexyl; and (ii) when Y¹ is1-methyl-4-pyrazolyl, 3-methylsulfonylphenyl or3-methylsulfonylaminophenyl, Z is other than cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In some embodiments,

Y¹ is CN, halogen, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, optionally substitutedC₃₋₆cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, aryl and heteroaryl,wherein the aliphatic or aromatic portion of Y¹ is each independentlyoptionally substituted with from 1-5 R¹ substituents;

each R¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₄-alkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkyl-C₁₋₄ alkyl or —R^(a), wherein R^(a) is selected fromhalogen, —CH═CH₂, —CN, —OH, —NH₂, —NO₂, —C(O)OH, —C(S)OH, —C(O)NH₂,—C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂,—OR^(b), —SR^(b), —OC(O)R^(b), —OC(S)R^(b), —C(O)R^(b), —C(S)R^(b),—C(O)OR^(b), —C(S)OR^(b), —S(O)R^(b), —S(O)₂R^(b), —C(O)NHR^(b),—C(S)NHR^(b), —C(O)NR^(b)R^(b), —C(S)NR^(b)R^(b), —S(O)₂NHR^(b),—S(O)₂NR^(b)R^(b), —C(NH)NHR^(b), —C(NH)NR^(b)R^(b), —NHC(O)R^(b),—NHC(S)R^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NHS(O)₂R^(b),—NR^(b)S(O)₂R^(b), —NHC(O)NHR^(b), —NHC(S)NHR^(b), —NR^(b)C(O)NH₂,—NR^(b)C(S)NH₂, —NR^(b)C(O)NHR^(b), —NR^(b)C(S)NHR^(b),—NHC(O)NR^(b)R^(b), —NHC(S)NR^(b)R^(b), —NR^(b)C(O)NR^(b)R^(b),—NR^(b)C(S)NR^(b)R^(b), —NHS(O)₂NHR^(b), —NR^(b)S(O)₂NH₂,—NR^(b)S(O)₂NHR^(b), —NHS(O)₂NR^(b)R^(b), —NR^(b)S(O)₂NR^(b)R^(b),—NHR^(b) or —NR^(b)R^(b),

each R^(b) is independently selected from the group consisting of C₁₋₆alkyl, halogen, —CN, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄-alkyl, —OH, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, aryl,aryl-C₁₋₄ alkyl, heteroaryl and heteroarylalkyl; or two R^(b)substituents when attached to the same nitrogen atom taken together withthe nitrogen atom form a three to eight-membered ring having from 0-2additional heteroatoms as ring members selected from N, O or S; whereinthe aliphatic or aromatic portion of R¹ is further optionallysubstituted with from 1-3 groups selected from C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl or —R^(c),

each R^(c) is independently selected from halogen, —CN, —OH, —CH═CH₂,—NH₂, —NO₂, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,—NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(d), —SR^(d), —OC(O)R^(d),—OC(S)R^(d), —C(O)R^(d), —C(S)R^(d), —C(O)OR^(d), —C(S)OR^(d),—S(O)R^(d), —S(O)₂R^(d), —C(O)NHR^(d), —C(S)NHR^(d), —C(O)NR^(d)R^(d),—C(S)NR^(d)R^(d), —S(O)₂NHR^(d), —S(O)₂NR^(d)R^(d), —C(NH)NHR^(d),—C(NH)NR^(d)R^(d), —NHC(O)R^(d), —NHC(S)R^(d), —NR^(d)C(O)R^(d),—NR^(d)C(S)R^(d), —NHS(O)₂R^(d), —NR^(d)S(O)₂R^(d), —NHC(O)NHR^(d),—NHC(S)NHR^(d), —NR^(d)C(O)NH₂, —NR^(d)C(S)NH₂, —NR^(d)C(O)NHR^(d),—NR^(d)C(S)NHR^(d), —NHC(O)NR^(d)R^(d), —NHC(S)NR^(d)R^(d),—NR^(d)C(O)NR^(d)R^(d), —NR^(d)C(S)NR^(d)R^(d), —NHS(O)₂NHR^(d),—NR^(d)S(O)₂NH₂, —NR^(d)S(O)₂NHR^(d), —NHS(O)₂NR^(d)R^(d),—NR^(d)S(O)₂NR^(d)R^(d), —NHR^(d), R^(f) or —NR^(d)R^(d),

each R^(d) is independently selected from C₁₋₆alkyl, arylalkyl, aryl,heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl or heterocycloalkylalkyl; and wherein the aromaticportion of R¹ is optionally substituted with from 1-3 substituentsindependently selected from R^(e),

R^(e) is selected from the group consisting of halogen, —CN, —CH═CH₂,—OH, —NH₂, —NO₂, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(f), —SR^(f),—OC(O)R^(f), —OC(S)R^(f), —C(O)R^(f), —C(S)R^(f), —C(O)OR^(f),—C(S)OR^(f), —S(O)R^(f), —S(O)₂R^(f), —C(O)NHR^(f), —C(S)NHR^(f),—C(O)NR^(f)R^(f), —C(S)NR^(f)R^(f), —S(O)₂NHR^(f), —S(O)₂NR^(f)R^(f),—C(NH)NHR^(f), —C(NH)NR^(f)R^(f), —NHC(O)R^(f), —NHC(S)R^(f),—NR^(f)C(O)R^(f), —NR^(f)C(S)R^(f), —NHS(O)₂R^(f), —NR^(f)S(O)₂R^(f),—NHC(O)NHR^(f), —NHC(S)NHR^(f), —NR^(f)C(O)NH₂, —NR^(f)C(S)NH₂,—NR^(f)C(O)NHR^(f), —NR^(f)C(S)NHR^(f), —NHC(O)NR^(f)R^(f),—NHC(S)NR^(f)R^(f), —NR^(f)C(O)NR^(f)R^(f), —NR^(f)C(S)NR^(f)R^(f),—NHS(O)₂NHR^(f), —NR^(f)S(O)₂NH₂, —NR^(f)S(O)₂NHR^(f),—NHS(O)₂NR^(f)R^(f), —NR^(f)S(O)₂NR^(f)R^(f), —NHR^(f), —NR^(f)R^(f) andR^(f),

R^(f) is C₁₋₆alkyl or aryl; or two adjacent R¹ groups on the aryl orheteroaryl ring together with the atoms to which they are attached forma 5- or 6-membered ring having from 0 to 2 additional heteroatomsselected from N, O or S, optionally substituted with from 1 to 3 R^(d)substituents;

R⁴ and R⁵ are each independently selected from the group consisting ofH, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl,wherein R⁴ or R⁵ is optionally substituted with from 1 to 3 membersindependently selected from C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl or R^(c); or

R⁴ and R⁵ taken together with the nitrogen atom to which they areattached form a four to eight membered ring having from 0-2 additionalheteroatoms as ring members selected from N, O or S, wherein said fourto eight membered ring is optionally substituted with from one to threegroups independently selected from C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl, aryl, arylalkyl or R^(e);and

R⁶, R⁷ and R⁸ are each independently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl or—X²R⁹; wherein the aliphatic or aromatic portion of R⁶, R⁷ and R⁸ areeach optionally substituted with from 1 to 3 members independentlyselected from the group consisting of C₃₋₈ cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and R^(e); or

any two of the R⁶, R⁷ and R⁸ groups taken together with the carbon atomto which they are attached form a 3 to 8-membered carbocyclic ring or a4 to 8-membered heterocyclic ring having from 1 to 2 heteroatoms as ringmembers selected from N, O or S, wherein the 3 to 8-membered carbocyclicring or the 4 to 8-membered heterocyclic ring is optionally substitutedwith from one to three groups independently selected from C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl optionally substituted withR^(e), C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl or R^(e).

In another aspect, the invention provides a composition. The compositionincludes a compound of any of formulas I to In, a compound as recited inany of the claims and described herein or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable excipient orcarrier. The invention also provides a composition, which includes acompound as recited in the claims and described herein, apharmaceutically acceptable excipient or carrier, and anothertherapeutic agent.

In yet another aspect, the invention provides a kit, which includes acompound of any of formulas I to In, a compound as recited in any of theclaims and described herein, or a pharmaceutically acceptable salt orsolvate thereof. The invention also provides a kit, which includes acomposition comprising a compound of formulas I to In, a compound asrecited in any of the claims and described herein, or a pharmaceuticallyacceptable salt or solvate thereof.

In another aspect, the invention provides a method for preparing acompound of formula (I) and any of the subgeneric formulas.

In still another aspect, the invention provides a method for treating asubject suffering from or at risk of a protein kinase mediated diseasesor conditions. The method includes administering to the subject aneffective amount of a compound of any of formulas I to In, a compound asrecited in any of the claims and described herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a composition comprising acompound of any of formulas I to In, a compound as recited in any of theclaims and described herein, or a pharmaceutically acceptable salt orsolvate thereof.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

As used herein the following definitions apply unless clearly indicatedotherwise:

It is noted here that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

“Halogen” or “halo” refers to all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Hydroxyl” or “hydroxy” refers to the group —OH.

“Thiol” refers to the group —SH.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon,having the number of carbon atoms designated (i.e. C₁₋₆ means one to sixcarbons). Representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbonatoms. Further representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, and the like. For each of the definitions herein (e.g., alkyl,alkoxy, alkylamino, alkylthio, alkylene, haloalkyl, arylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl), when a prefixis not included to indicate the number of carbon atoms in an alkylportion, the alkyl moiety or portion thereof will have 12 or fewer mainchain carbon atoms or 8 or fewer main chain carbon atoms or 6 or fewermain chain carbon atoms. For example, C₁₋₈ alkyl refers to a straight orbranched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms andincludes, but are not limited to, C₁₋₂ alkyl, C₁₋₄ alkyl, C₂₋₆ alkyl,C₂₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₇ alkyl, C₂₋₇ alkyl and C₃₋₆alkyl. “Fluoro substituted alkyl” denotes a alkyl group substituted withone or more fluoro atoms, such as perfluoroalkyl, where preferably thelower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2,or 3 fluoro atoms. While it is understood that substitutions areattached at any available atom to produce a stable compound, whenoptionally substituted alkyl is an R group of a moiety such as —OR (e.g.alkoxy), —SR (e.g. thioalkyl), —NHR (e.g. alkylamino), —C(O)NHR, and thelike, substitution of the alkyl R group is such that substitution of thealkyl carbon bound to any O, S, or N of the moiety (except where N is aheteroaryl ring atom) excludes substituents that would result in any O,S, or N of the substituent (except where N is a heteroaryl ring atom)being bound to the alkyl carbon bound to any O, S, or N of the moiety.

The term “alkylene” by itself or as part of another substituent means alinear or branched saturated divalent hydrocarbon moiety derived from analkane having the number of carbon atoms indicated in the prefix. Forexample, (i.e., C₁₋₆ means one to six carbons; C₁₋₆ alkylene is meant toinclude methylene, ethylene, propylene, 2-methylpropylene, pentylene,hexylene and the like). C₁₋₄ alkylene includes methylene —CH₂—, ethylene—CH₂CH₂—, propylene —CH₂CH₂CH₂—, and isopropylene —CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —CH₂—(CH₂)₂CH₂—, —CH₂—CH(CH₃)CH₂—, —CH₂—C(CH₃)₂—,—CH₂—CH₂CH(CH₃)—. Typically, an alkyl (or alkylene) group will have from1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer,or 6 or fewer carbon atoms being preferred in the present invention.When a prefix is not included to indicate the number of carbon atoms inan alkylene portion, the alkylene moiety or portion thereof will have 12or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms,6 or fewer main chain carbon atoms or 4 or fewer main chain carbonatoms.

The term “alkenylene” refers to a linear bivalent hydrocarbon moiety ora branched monovalent hydrocarbon moiety having the number of carbonatoms indicated in the prefix and containing at least one double bond.For example, i.e., C₂₋₆ means two to six carbons; C₂₋₆ alkenylene ismeant to include, but are not limited to, —CH═CH—, —CH₂—CH═CH—,—CH₂—CH═C(CH₃)—, —CH═CH—CH═CH—, and the like). Similarly, the term“alkynylene” refers to a linear bivalent hydrocarbon moiety or abranched monovalent hydrocarbon moiety containing at least one triplebond and having the number of carbon atoms indicated in the prefix. Forexample, (i.e., C₂₋₆ means two to six carbons; C₂₋₆ alkynlene is meantto include, but are not limited to, —C≡C—, —C≡CCH₂—, —CH₂—C≡CCH₂—,—C≡CCH(CH₃)—, and the like. When a prefix is not included to indicatethe number of carbon atoms in an alkenylene or alkynlene portion, thealkenylene moiety or portion thereof will have 12 or fewer main chaincarbon atoms or 8 or fewer main chain carbon atoms or 6 or fewer mainchain carbon atoms, or 4 or fewer main chain carbon atoms.

“Cycloalkyl” by itself or as part of another substituent, refers tosaturated or unsaturated, non-aromatic monocyclic, bicyclic or tricycliccarbon ring systems of 3-10, also 3-8, more preferably 3-6, ring membersper ring, such as cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl,adamantyl, and the like. Cycloalkyl refers to hydrocarbon rings havingthe indicated number of ring atoms (e.g., C₃₋₈ cycloalkyl means three toeight ring carbon atoms)

“Cycloalkylalkyl” refers to an -(alkylene)-cycloalkyl group wherealkylene as defined herein has the indicated number of carbon atoms orif unspecified having six or fewer, preferably four or fewer main chaincarbon atoms; and cycloalkyl is as defined herein has the indicatednumber of carbon atoms. C₃₋₈cycloalkylalkyl is meant to have 3 to 8 ringcarbon atoms. Exemplary cycloalkylalkyl include, e.g.,cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, and thelike.

“Haloalkyl,” is meant to include alkyl substituted by one to sevenhalogen atoms. Haloalkyl includes monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁₋₆ haloalkyl” is meant to include trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

“Haloalkoxy” refers to a —O-haloalkyl group, where haloalkyl is asdefined herein, e. g., trifluoromethoxy, 2,2,2-trifluoroethoxy,difluoromethoxy, and the like.

“Alkoxy” refers to a —O-alkyl group, where alkyl is as defined herein.“Cycloalkoxy” refers to a —O-cycloalkyl group, where cycloalkyl is asdefined herein. “Fluoro substituted alkoxy” denotes alkoxy in which thealkyl is substituted with one or more fluoro atoms, where preferably thealkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3fluoro atoms. While it is understood that substitutions on alkoxy areattached at any available atom to produce a stable compound,substitution of alkoxy is such that O, S, or N (except where N is aheteroaryl ring atom), are not bound to the alkyl carbon bound to thealkoxy O. Further, where alkoxy is described as a substituent of anothermoiety, the alkoxy oxygen is not bound to a carbon atom that is bound toan O, S, or N of the other moiety (except where N is a heteroaryl ringatom), or to an alkene or alkyne carbon of the other moiety.

“Amino” or “amine” denotes the group —NH₂.

“Alkylamino” refers to a —NH-alkyl group, where alkyl is as definedherein. Exemplary alkylamino groups include CH₃NH—, ethylamino, and thelike.

“Dialkylamino” refers to a —N(alkyl)(alkyl) group, where each alkyl isindependently as defined herein. Exemplary dialkylamino groups includedimethylamino, diethylamino, ethylmethylamino, and the like.

“Cycloalkylamino” denotes the group —NR^(dd)R^(ee), where R^(dd) andR^(ee) combine with the nitrogen to form a 5-7 membered heterocycloalkylring, where the heterocycloalkyl may contain an additional heteroatomwithin the ring, such as O, N, or S, and may also be further substitutedwith alkyl. Alternatively, “cycloalkylamino” refers to a —NH-cycloalkylgroup, where cycloalkyl is as defined herein.

“Alkylthio” refers to —S-alkyl, where alkyl is as defined herein.Exemplary alkylthio groups include CH₃S—, ethylthio, and the like.

“Aryl” by itself or as part of another substituent refers to amonocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbonmoiety containing 6 to 14 ring carbon atoms. Non-limiting examples ofunsubstituted aryl groups include phenyl, 1-naphthyl, 2-naphthyl and4-biphenyl. Exemplary aryl group, such as phenyl or naphthyl, which maybe optionally fused with a cycloalkyl of preferably 5-7, more preferably5-6, ring members.

“Arylalkyl” refers to -(alkylene)-aryl, where the alkylene group is asdefined herein and has the indicated number of carbon atoms, or ifunspecified having six or fewer main chain carbon atoms or four or fewermain chain carbon atoms; and aryl is as defined herein. Examples ofarylalkyl include benzyl, phenethyl, and the like.

“Heteroaryl” by itself or as part of another substituent refers to amonocyclic aromatic ring structure containing 5 or 6 ring atoms, or abicyclic aromatic group having 8 to 10 atoms, containing one or more,preferably 1-4, more preferably 1-3, even more preferably 1-2,heteroatoms independently selected from the group consisting of O, S,and N. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable compound is produced. Examples ofheteroaryl groups include, but are not limited to, pyridinyl,pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl,oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl,triazinyl, quinoxalinyl, cinnolinyl, phthalaziniyl, benzotriazinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzothienyl, quinolyl, isoquinolyl, indazolyl,pteridinyl and thiadiazolyl. “Nitrogen containing heteroaryl” refers toheteroaryl wherein any heteroatoms are N.

“Heteroarylalkyl” refers to -(alkylene)-heteroaryl, where the alkylenegroup is as defined herein and has the indicated number of carbon atoms,or if unspecified having six or fewer main chain carbon atoms or four orfewer main chain carbon atoms; and heteroaryl is as defined herein.Examples of heteroarylalkyl include 2-pyridylmethyl, 2-thiazolylethyl,and the like.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group that contains from one to five heteroatoms selectedfrom N, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized, theremaining ring atoms being C, where one or two C atoms may optionally bereplaced by a carbonyl. The heterocycloalkyl may be a monocyclic, abicyclic or a polycylic ring system of 3 to 12, preferably 4 to 10 ringatoms, more preferably 5 to 8 ring atoms in which one to five ring atomsare heteroatoms selected from —N═, —N—, —O—, —S—, —S(O)—, or —S(O)₂— andfurther wherein one or two ring atoms are optionally replaced by a—C(O)— group. The heterocycloalkyl can also be a heterocyclic alkyl ringfused with a cycloalkyl, an aryl or a heteroaryl ring. Non limitingexamples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl,imidazolidinyl, pyrazolidinyl, butyrolactam moiety, valerolactam moiety,imidazolidinone moiety, hydantoin, dioxolane moiety, phthalimide moiety,piperidine, 1,4-dioxane moiety, morpholinyl, thiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl,pyranyl, pyridine moiety, 3-pyrrolinyl, thiopyranyl, pyrone moiety,tetrahydrofuranyl, tetrahydrothiophenyl, quinuclidinyl, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

“Heterocycloalkylalkyl” refers to -(alkylene)-heterocycloalkyl, wherethe alkylene group is as defined herein and has the indicated number ofcarbon atoms, or if unspecified having six or fewer main chain carbonatoms or four or fewer main chain carbon atoms; and heterocycloalkyl isas defined herein. Examples of heterocycloalkylalkyl include2-pyridylmethyl, 2-thiazolylethyl, and the like.

The substituents for alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl,cycloalkylalkyl, alkylene, alkenylene, alkynlene include, but are notlimited to, R′, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH,—C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂,—C(NH)NH₂, —OR′, —SR′, —OC(O)R′, —OC(S)R′, —C(O)R′, —C(S)R′, —C(O)OR′,—C(S)OR′, —S(O)R′, —S(O)₂R′, —C(O)NHR′, —C(S)NHR′, —C(O)NR′R″,—C(S)NR′R″, —S(O)₂NHR′, —S(O)₂NR′R″, —C(NH)NHR′, —C(NH)NR′R″, —NHC(O)R′,—NHC(S)R′, —NR″C(O)R′, —NR′C(S)R″, —NHS(O)₂R′, —NR′S(O)₂R″, —NHC(O)NHR′,—NHC(S)NHR′, —NR′C(O)NH₂, —NR″C(S)NH₂, —NR″C(O)NHR′, —NR′C(S)NHR″,—NHC(O)NR′R″, —NHC(S)NR′R″, —NR′C(O)NR″R′″, —NR′″C(S)NR′R″,—NHS(O)₂NHR′, —NR′S(O)₂NH₂, —NR′S(O)₂NHR″, —NHS(O)₂NR′R″,—NR′S(O)₂NR″R′″, —NHR′, and —NR′R″ in a number ranging from zero to(2m′+1), where m′ is the total number of carbon atoms in such group. R′,R″ and R′″ each independently refer to hydrogen, C₁₋₈ alkyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylsubstituted with 1-3 halogens, C₁₋₈ alkoxy, haloalkyl, haloalkoxy orC₁₋₈ thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkyl groups. When R′and R″ are attached to the same nitrogen atom, they can be combined withthe nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. Forexample, —NR′R″ is meant to include 1-pyrrolidinyl and 4-morpholinyl.R′, R″ and R′″ can be further substituted with R^(a1), halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a1), —SR^(a1),—OC(O)R^(a1), —OC(S)R^(a1), —C(O)R^(a1), —C(S)R^(a1), —C(O)OR^(a1),—C(S)OR^(a1), —S(O)R^(a1), —S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1),—C(O)NR^(a1)R^(a2), —C(S)NR^(a1)R^(a2), —S(O)₂NHR^(a1),—S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1), —C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1),—NHC(S)R^(a1), —NR^(a2)C(O)R^(a1), —NR^(a1)C(S)R^(a2), —NHS(O)₂R^(a1),—NR^(a1)S(O)₂R^(a2), —NHC(O)NHR^(a1), —NHC(S)NHR^(a1), —NR^(a1)C(O)NH₂,—NR^(a1)C(S)NH₂, —NR^(a1)C(O)NHR^(a2), —NR^(a1)C(S)NHR^(a2),—NHC(O)NR^(a1)R^(a2), —NHC(S)NR^(a1)R^(a2), —NR^(a1)C(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(a1)R^(a2), —NHS(O)₂NHR^(a1), —NR^(a1)S(O)₂NH₂,—NR^(a1)S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a2),—NR^(a1)S(O)₂NR^(a2)R^(a3), —NHR^(a1), and —NR^(a1)R^(a2) in a numberranging from zero to (2n′+1), where n′ is the total number of carbonatoms in such group. R^(a1), R^(a2) and R^(a3) each independently referto hydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁₋₈ alkoxy,haloalkyl, haloalkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups. R^(a1), R^(a2) and R^(a3) can be furthersubstituted with R^(b1), halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(b1), —SR^(b1), —OC(O)R^(b1), —OC(S)R^(b1),—C(O)R^(b), —C(S)R^(b1), —C(O)OR^(b1), —C(S)OR^(b1), —S(O)R^(b1),—S(O)₂R^(b1), —C(O)NHR^(b1), —C(S)NHR^(b1), —C(O)NR^(b1)R^(b2),—C(S)NR^(b1)R^(b2), —S(O)₂NHR^(b1), —S(O)₂NR^(b1)R^(b2), —C(NH)NHR^(b1),—C(NH)NR^(b1)R^(b2), —NHC(O)R^(b1), —NHC(S)R^(b1), —NR^(b2)C(O)R^(b1),—NR^(b1)C(S)R^(b2), —NHS(O)₂R^(b1), —NR^(b1)S(O)₂R^(b2),—NHC(O)NHR^(b1), —NHC(S)NHR^(b1), —NR^(b1)C(O)NH₂, —NR^(b1)C(S)NH₂,—NR^(b1)C(O)NHR^(b2), —NR^(b1)C(S)NHR^(b2), —NHC(O)NR^(b1)R^(b2),—NHC(S)NR^(b1)R^(b2), —NR^(b1)C(O)NR^(b2)R^(b3),—NR^(b3)C(S)NR^(b1)R^(b2), —NHS(O)₂NHR^(b1), —NR^(b1)S(O)₂NH₂,—NR^(b1)S(O)₂NHR^(b2), —NHS(O)₂NR^(b1)R^(b2),—NR^(b1)S(O)₂NR^(b2)R^(b3), —NHR^(b1), and —NR^(b1)R^(b2) in a numberranging from zero to (2p′+1), where p′ is the total number of carbonatoms in such group. R^(b1), R^(b2) and R^(b3) each independently referto hydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁₋₈ alkoxy,haloalkyl, haloalkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups.

Substituents for the aryl and heteroaryl groups are varied and aregenerally selected from: R′, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR′, —SR′, —OC(O)R′, —OC(S)R′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —S(O)R′, —S(O)₂R′, —C(O)NHR′, —C(S)NHR′,—C(O)NR′R″, —C(S)NR′R″, —S(O)₂NHR′, —S(O)₂NR′R″, —C(NH)NHR′,—C(NH)NR′R″, —NHC(O)R′, —NHC(S)R′, —NR″C(O)R′, —NR′C(S)R″, —NHS(O)₂R′,—NR′S(O)₂R″, —NHC(O)NHR′, —NHC(S)NHR′, —NR′C(O)NH₂, —NR′C(S)NH₂,—NR′C(O)NHR″, —NR′C(S)NHR″, —NHC(O)NR′R″, —NHC(S)NR′R″, —NR′C(O)NR″R′″,—NR′″C(S)NR′R″, —NHS(O)₂NHR′, —NR′S(O)₂NH₂, —NR′S(O)₂NHR″,—NHS(O)₂NR′R″, —NR′S(O)₂NR″R′″, —NHR′, —NR′R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, haloalkyl, haloalkoxy, C₁₋₈ alkyl, C₃₋₆ cycloalkyl,cycloalkylalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, aryl-C₁₋₄ alkyl, and aryloxy-C₁₋₄ alkyl.Other suitable substituents include each of the above aryl substituentsattached to a ring atom by an alkylene tether of from 1-4 carbon atoms.R′, R″ and R′″ can be further substituted with R^(a1), halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a1), —SR^(a1),—OC(O)R^(a1), —OC(S)R^(a1), —C(O)R^(a1), —C(S)R^(a1), —C(O)OR^(a1),—C(S)OR^(a1), —S(O)R^(a1), —S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1),—C(O)NR^(a1)R^(a2), —C(S)NR^(a1)R^(a2), —S(O)₂NHR^(a1),—S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1), —C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1),—NHC(S)R^(a1), —NR^(a2)C(O)R^(a1), —NR^(a1)C(S)R^(a2), —NHS(O)₂R^(a1),—NR^(a1)S(O)₂R^(a2), —NHC(O)NHR^(a1), —NHC(S)NHR^(a1), —NR^(a1)C(O)NH₂,—NR^(a1)C(S)NH₂, —NR^(a1)C(O)NHR^(a2), —NR^(a1)C(S)NHR^(a2),—NHC(O)NR^(a1)R^(a2), —NHC(S)NR^(a1)R^(a2), —NR^(a1)C(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(a1)R^(a2), —NHS(O)₂NHR^(a1), —NR^(a1)S(O)₂NH₂,—NR^(a1)S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a2),—NR^(a1)S(O)₂NR^(a2)R^(a3), —NHR^(a1), —NR^(a2), —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R^(a1), R^(a2) and R^(a3) are each independentlyselected from hydrogen, haloalkyl, haloalkoxy, C₁₋₈ alkyl, C₃₋₆cycloalkyl, cycloalkylalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, aryl-C₁₋₄ alkyl, or aryloxy-C₁₋₄alkyl. Other suitable substituents include each of the above arylsubstituents attached to a ring atom by an alkylene tether of from 1-4carbon atoms.

When two substituents are present on adjacent atoms of a substitutedaryl or a substituted heteroaryl ring, such substituents may optionallybe replaced with a substituent of the formula —T-C(O)—(CH₂)_(q)—U—,wherein T and U are independently —NH—, —O—, —CH₂— or a single bond, andq is an integer of from 0 to 2. Alternatively, when two substituents arepresent on adjacent atoms of a substituted aryl or a substitutedheteroaryl ring, such substituents may optionally be replaced with asubstituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, when two substituents are present on adjacent atoms of asubstituted aryl or a substituted heteroaryl ring, such substituents mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in T. W. Greene and P. G.Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006),Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrison andHarrison et al., COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8(John Wiley and Sons. 1971-1996). Representative amino protecting groupsinclude formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl(CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS),phenylsulphonyl and the like (see also, Boyle, A. L. (Editor),carbamates, amides, N-sulfonyl derivatives, groups of formula —C(O)OR,wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl,CH₂═CHCH₂—, and the like, groups of the formula —C(O)R′, wherein R′ is,for example, methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula —SO₂R″, wherein R″ is, for example, tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACIDCHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000).

As used herein, the term “composition” refers to a formulation suitablefor administration to an intended animal subject for therapeuticpurposes that contains at least one pharmaceutically active compound andat least one pharmaceutically acceptable carrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectibles.

“Pharmaceutically-acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically-acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Salts derivedfrom pharmaceutically-acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

By “assaying” is meant the creation of experimental conditions and thegathering of data regarding a particular result of the exposure tospecific experimental conditions. For example, enzymes can be assayedbased on their ability to act upon a detectable substrate. A compoundcan be assayed based on its ability to bind to a particular targetmolecule or molecules.

As used herein, the terms “ligand” and “modulator” are used equivalentlyto refer to a compound that changes (i.e., increases or decreases) theactivity of a target biomolecule, e.g., an enzyme such as a kinase.Generally a ligand or modulator will be a small molecule, where “smallmolecule refers to a compound with a molecular weight of 1500 daltons orless, or preferably 1000 daltons or less, 800 daltons or less, or 600daltons or less. Thus, an “improved ligand” is one that possesses betterpharmacological and/or pharmacokinetic properties than a referencecompound, where “better” can be defined by one skilled in the relevantart for a particular biological system or therapeutic use.

The term “binds” in connection with the interaction between a target anda potential binding compound indicates that the potential bindingcompound associates with the target to a statistically significantdegree as compared to association with proteins generally (i.e.,non-specific binding). Thus, the term “binding compound” refers to acompound that has a statistically significant association with a targetmolecule. Preferably a binding compound interacts with a specifiedtarget with a dissociation constant (K_(D)) of 1 mM or less, 1 □M orless, 100 nM or less, 10 nM or less, or 1 nM or less.

In the context of compounds binding to a target, the terms “greateraffinity” and “selective” indicates that the compound binds more tightlythan a reference compound, or than the same compound in a referencecondition, i.e., with a lower dissociation constant. In someembodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50,100, 200, 400, 500, 1000, or 10,000-fold greater affinity.

As used herein in connection with compounds of the invention, the term“synthesizing” and like terms means chemical synthesis from one or moreprecursor materials. Further, by “assaying” is meant the creation ofexperimental conditions and the gathering of data regarding a particularresult of the experimental conditions. For example, enzymes can beassayed based on their ability to act upon a detectable substrate. Acompound or ligand can be assayed based on its ability to bind to aparticular target molecule or molecules.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with a particular biomolecule such as a protein kinase. Forexample, an agonist or antagonist of a particular biomolecule modulatesthe activity of that biomolecule, e.g., an enzyme, by either increasing(e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor)the activity of the biomolecule, such as an enzyme. Such activity istypically indicated in terms of an inhibitory concentration (IC₅₀) orexcitation concentration (EC₅₀) of the compound for an inhibitor oractivator, respectively, with respect to, for example, an enzyme.

“Prodrugs” means any compound which releases an active parent drugaccording to Formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula I are prepared bymodifying functional groups present in the compound of Formula I in sucha way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs may be prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of Formula I wherein a hydroxy,amino, carboxyl or sulfhydryl group in a compound of Formula I is bondedto any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), amides, guanidines, carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds ofFormula I, and the like. Preparation, selection, and use of prodrugs isdiscussed in T. Higuchi and V. Stella, “Pro-drugs as Novel DeliverySystems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, each of which are hereby incorporated by referencein their entirety.

“Tautomer” means compounds produced by the phenomenon wherein a protonof one atom of a molecule shifts to another atom. See, Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms and Structures, FourthEdition, John Wiley & Sons, pages 69-74 (1992). The tautomers also referto one of two or more structural isomers that exist in equilibrium andare readily converted from one isomeric form to another. Examples ofinclude keto-enol tautomers, such as acetone/propen-2-ol, imine-enaminetautomers and the like, ring-chain tautomers, such asglucose/2,3,4,5,6-pentahydroxy-hexanal and the like, the tautomericforms of heteroaryl groups containing a —N═C(H)—NH— ring atomarrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles,and tetrazoles. Where the compound contains, for example, a keto oroxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’)can occur. The compounds described herein may have one or more tautomersand therefore include various isomers. A person of ordinary skill in theart would recognize that other tautomeric ring atom arrangements arepossible. All such isomeric forms of these compounds are expresslyincluded in the present invention.

“Isomers” mean compounds having identical molecular formulae but differin the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.“Stereoisomer” and “stereoisomers” refer to compounds that exist indifferent stereoisomeric forms if they possess one or more asymmetriccenters or a double bond with asymmetric substitution and, therefore,can be produced as individual stereoisomers or as mixtures.Stereoisomers include enantiomers and diastereomers. Stereoisomers thatare not mirror images of one another are termed “diastereomers” andthose that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”. Unless otherwise indicated, the descriptionis intended to include individual stereoisomers as well as mixtures. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art (see discussion in Chapter 4 ofADVANCED ORGANIC CHEMISTRY, 6th edition J. March, John Wiley and Sons,New York, 2007) differ in the chirality of one or more stereocenters.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. “Hydrate” refers toa complex formed by combination of water molecules with molecules orions of the solute. “Solvate” refers to a complex formed by combinationof solvent molecules with molecules or ions of the solute. The solventcan be an organic compound, an inorganic compound, or a mixture of both.Solvate is meant to include hydrate. Some examples of solvents include,but are not limited to, methanol, N,N-dimethylformamide,tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Certain compounds of the presentinvention may exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the uses contemplated bythe present invention and are intended to be within the scope of thepresent invention.

In the context of the use, testing, or screening of compounds that areor may be modulators, the term “contacting” means that the compound(s)are caused to be in sufficient proximity to a particular molecule,complex, cell, tissue, organism, or other specified material thatpotential binding interactions and/or chemical reaction between thecompound and other specified material can occur.

As used herein, the term “subject” refers to a living organism that istreated with compounds as described herein, including, but not limtedto, any mammal, such as a human, other primates, sports animals, animalsof commercial interest such as cattle, farm animals such as horses, orpets such as dogs and cats.

“Solid form” refers to a solid preparation (i.e. a preparation that isneither gas nor liquid) of a pharmaceutically active compound that issuitable for administration to an intended animal subject fortherapeutic purposes. The solid form includes any complex, such as asalt, co-crystal or an amorphous complex, as well as any polymorph ofthe compound. The solid form may be substantially crystalline,semi-crystalline or substantially amorphous. The solid form may beadministered directly or used in the preparation of a suitablecomposition having improved pharmaceutical properties. For example, thesolid form may be used in a formulation comprising at least onepharmaceutically acceptable carrier or excipient.

“Pain” or a “pain condition” can be acute and/or chronic pain,including, without limitation, arachnoiditis; arthritis (e.g.osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout);back pain (e.g. sciatica, ruptured disc, spondylolisthesis,radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g.migraine, cluster headaches, tension headaches); head and facial pain(e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia;hyperpathia; inflammatory pain (e.g. pain associated with irritablebowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, cystitis, pain from bacterial, fungal or viral infection);keloid or scar tissue formation; labor or delivery pain; muscle pain(e.g. as a result of polymyositis, dermatomyositis, inclusion bodymyositis, repetitive stress injury (e.g. writer's cramp, carpal tunnelsyndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g.fibromyalgia); neuropathic pain (e.g. diabetic neuropathy, causalgia,entrapment neuropathy, brachial plexus avulsion, occipital neuralgia,gout, reflex sympathetic dystrophy syndrome, phantom limb orpost-amputation pain, postherpetic neuralgia, central pain syndrome, ornerve pain resulting from trauma (e.g. nerve injury), disease (e.g.diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis,neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, or cancer treatment); painassociated with skin disorders (e.g. shingles, herpes simplex, skintumors, cysts, neurofibromatosis); sports injuries (e.g. cuts, sprains,strains, bruises, dislocations, fractures, spinal chord, head); spinalstenosis; surgical pain; tactile allodynia; temporomandibular disorders;vascular disease or injury (e.g. vasculitis, coronary artery disease,reperfusion injury (e.g. following ischemia, stroke, or myocardialinfarcts)); other specific organ or tissue pain (e.g. ocular pain,corneal pain, bone pain, heart pain, visceral pain (e.g. kidney,gallbladder, gastrointestinal), joint pain, dental pain, pelvichypersensitivity, pelvic pain, renal colic, urinary incontinence); otherdisease associated pain (e.g. sickle cell anemia, AIDS, herpes zoster,psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease(COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn,gastroesophageal reflux disorder, stomach and duodenal ulcers,functional dyspepsia, bone resorption disease, osteoporosis, cerebralmalaria, bacterial meningitis); or pain due to graft v. host rejectionor allograft rejections.

“Unit dosage form” refers to a composition intended for a singleadministration to treat a subject suffering from a disease or medicalcondition. Each unit dosage form typically comprises each of the activeingredients of this invention plus pharmaceutically acceptableexcipients. Examples of unit dosage forms are individual tablets,individual capsules, bulk powders, liquid solutions, ointments, creams,eye drops, suppositories, emulsions or suspensions. Treatment of thedisease or condition may require periodic administration of unit dosageforms, for example: one unit dosage form two or more times a day, onewith each meal, one every four hours or other interval, or only one perday. The expression “oral unit dosage form” indicates a unit dosage formdesigned to be taken orally.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

As used herein in connection with amino acid or nucleic acid sequence,the term “isolate” indicates that the sequence is separated from atleast a portion of the amino acid and/or nucleic acid sequences withwhich it would normally be associated.

In connection with amino acid or nucleic sequences, the term “purified”indicates that the subject molecule constitutes a significantly greaterproportion of the biomolecules in a composition than the proportionobserved in a prior composition, e.g., in a cell culture. The greaterproportion can be 2-fold, 5-fold, 10-fold, or more than 10-fold, withrespect to the proportion found in the prior composition.

The invention also embraces isotopically-labeled compounds of thepresent invention which are identical to those recited herein, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to ²H(deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S,³⁶Cl, and ¹²⁵I. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition or its isotopes,such as deuterium (D) or tritium (³H). Certain isotopically-labeledcompounds of the present invention (e.g., those labeled with .sup.3H and.sup. 14C) are useful in compound and/or substrate tissue distributionassays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes areuseful for their ease of preparation and detectability. Further,substitution with heavier isotopes such as deuterium (i.e., ²H) mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence may be preferred in some circumstances.Isotopically labeled compounds of the present invention can generally beprepared by following procedures analogous to those disclosed in theSchemes and in the Examples herein below, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.

II. General

The present invention concerns compounds of Formula I and allsub-generic formulae, compounds as recited in the claims, and compoundsdescribed herein that are modulators of protein kinases, for examplewithout limitation, the compounds are modulators of at least one of thekinases selected from the group consisting of ABL1, ABL2, ACK, ADRBK1,AKT1, AMPK_A2, A-RAF, ARKS, Aurora_A-C, BMX, CDC42_BPA, CAMK2A,CDK5_p35, CSF1R, DYRKIB, EPHA5, EPHA8, EPHB4, FES, FLT3, FYN, GSK3β,JAK1, KDR, KIT, MAP4K2, MAPK3, MARK2, MARK4, MATK, MET, MINK1, NEK1,NEK2, PAK3, PAK6, PDGFRb, PHKG1, PKC_beta_I, PKC_beta_II, PKC_delta,PKC_gamma, PKC_zeta, SRC, STK24, STK4, ACVR1B_(ALK4), ADRBK2_(GRK3),AKT2_(PKBb), AKT3_(PKBg), ALK, AMPK_A1/B1/G1, ARK5, ASK1, AXL,BRSK1_(SAD1), BrSK2, BTK, CAMK1, CAMK1D, CAMK2A, CAMK2B, CAMK2D,CaMKIdelta, CaMKIIbeta, CaMKIIdelta, CaMKIIgamma, CDC42_BPB,CDK1/CyclinB, CDK2/CyclinA, CDK2/cyclinE, CDK3/cyclinE, CDK5_p25,CDK6/cyclinD3, CDK7/CyclinH/MNAT1, CDK9/CyclinT1, CHEK1, CHEK2,CK1delta, CK1gamma1, CK1gamma2, CK1gamma3, CK2alpha2, CLK1, CLK2, CLK3,CSNK1A1, CSNK1D, CSNK1E, CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2,DAPK1, DAPK2, DAPK3_(ZIPK), DCAMKL2_(DCK2), DDR2, DMPK, DRAK1, DYRKIA,DYRK2, DYRK3, DYRK4, EEF2K, EGFR, EPHA1, EPHA2, EPHA3 EPHA4, EphA7,EPHB1, EPHB2, EPHB3, ERBB2, ERBB4, FER, FGFR1, FGFR2, FGFR3, FGFR4,FLT1, FLT4, FRAP1, GCK, GRK4, GRK5, GRK6, GRK7, GSK3A, GSK3B, Haspin,HCK, Hck activated, HIPK, HIPK2, HIPK3, HIPK4, IGF1R, IGF-1R-activated,IKBKB, IKBKE, IKKalpha, IKKbeta, INSR, INSRR, IR-activated, IRAK1,IRAK4, ITK, JAK2, JAK2_JH1_JH2, JAK3, JNKlalphal, JNK2alpha2,Lck-activated, LIMK1, LKB1, LOK, LTK, MAP2K1, MAP2K2, MAP2K6, MAP3K8,MAP3K9, MAP4K4, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK2,MAPK8, MAPK9, MAPKAPK2, MAPKAPK3, MAPKAPK5, MARK1, MARK3, MELK, MERTK,MKK7beta, MLCK, MRCKalpha, MRCKbeta, MST1R, MST4, mTOR/FKBP 12, MUSK,NEK3, NEK4, NEK6, NEK7, NEK9, NLK, NTRK1, NTRK2, NTRK3, PAK2, PAK4,PAK7_(KIAA1264), PAR-1Balpha, PASK, PDGFRalpha, PDGFRbeta, PDK1, PHKG2,PhKgamma2, PIK3CA/PIK3R1, PIK3CG,) PIM1, PIM2, Pim-3, PKBalpha, PKBbeta,PKBgamma, PKCalpha, PKCbetaI, PKCbetaII, PKCdelta, PKCepsilon, PKCeta,PKCgamma, PKCiota, PKCmu, PKCtheta, PKCzeta, PKGlalpha, PKGlbeta, PKN1,PLK2, PLK3, PRK2, PRKACA, PRKCA, PRKCE, PRKCH, PRKCI, PRKCN, PRKCQ,PRKD1, PRKD2, PRKG1, PRKG2, PRKX, PTK2, PTK2B, RET, RIPK2, ROCK1, ROCK2,ROS1, RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA4, RPS6KA5, RPS6KA6, RPS6KB1,SGK, SGK2, SGKL, SIK, SNF1LK2, Snk, SRPK1, SRPK2, STK22B, STK22D, STK23,STK25, STK3, STK33, SYK, TAK1, TAO3, TAOK2, TBK1, Tec activated, TEK,TLK2, Txk, TYK2, TYRO3, ULK2, ULK3, VRK2, WNK2, WNK3, and ZAP70 and theuse of such compounds in the treatment of diseases or conditions. Insome embodiments, the kinases have less than 20% Inhibition at 1 μM. Inother embodiments, the kinases have less than 10% Inhibition at 1 μM.

III. Compounds

In one aspect, the present invention provides compounds of formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, tautomers andisomers thereof, wherein the substituents are as defined in the Summaryof the Invention.

In some embodiments of compounds of formula (I), Y¹ is as defined in thesummary of the invention. The All the other substituents of formula (I)are as defined in any of the embodiments described herein. In somepreferred embodiments, the compounds have molecular weights less than600, more preferably, the compounds have molecular weights less than550. In other preferred embodiments, the compounds have molecularweights less than 500.

In some embodiments of compounds of formula (I), Y¹ is CN, halogen, —OH,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, aryl or heteroaryl, wherein the aliphatic or aromaticportion of Y¹ is each independently optionally substituted with from 1-5R¹ substituents; each R¹ is independently selected from C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄-alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkyl-C₁₋₄ alkyl or —R^(a), wherein R^(a)is selected from halogen, —CH═CH₂, —CN, —OH, —NH₂, —NO₂, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(b), —SR^(b), —OC(O)R^(b), —OC(S)R^(b),—C(O)R^(b), —C(S)R^(b), —C(O)OR^(b), —C(S)OR^(b), —S(O)R^(b),—S(O)₂R^(b), —C(O)NHR^(b), —C(S)NHR^(b), —C(O)NR^(b)R^(b),—C(S)NR^(b)R^(b), —S(O)₂NHR^(b), —S(O)₂NR^(b)R^(b), —C(NH)NHR^(b),—C(NH)NR^(b)R^(b), —NHC(O)R^(b), —NHC(S)R^(b), —NR^(b)C(O)R^(b),—NR^(b)C(S)R^(b), —NHS(O)₂R^(b), —NR^(b)S(O)₂R^(b), —NHC(O)NHR^(b),—NHC(S)NHR^(b), —NR^(b)C(O)NH₂, —NR^(b)C(S)NH₂, —NR^(b)C(O)NHR^(b),—NR^(b)C(S)NHR^(b), —NHC(O)NR^(b)R^(b), —NHC(S)NR^(b)R^(b),—NR^(b)C(O)NR^(b)R^(b), —NR^(b)C(S)NR^(b)R^(b), —NHS(O)₂NHR^(b),—NR^(b)S(O)₂NH₂, —NR^(b)S(O)₂NHR^(b), —NHS(O)₂NR^(b)R^(b),—NR^(b)S(O)₂NR^(b)R^(b), —NHR^(b) or —NR^(b)R^(b), wherein each R^(b) isindependently selected from the group consisting of C₁₋₆alkyl, halogen,—CN, C₁₋₆alkoxy, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄-alkyl, —OH,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, aryl, aryl-C₁₋₄alkyl, heteroaryl andheteroarylalkyl; or two R^(b) substituents when attached to the samenitrogen atom taken together with the nitrogen atom form a three toeight-membered ring having from 0-2 additional heteroatoms as ringmembers selected from N, O or S; wherein the aliphatic or aromaticportion of R¹ is further optionally substituted with from 1-3 groupsselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl or —R^(c), wherein each R^(c) isindependently selected from halogen, —CH═CH₂, —CN, —OH, —NH₂, —NO₂,—C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(d), —SR^(d), —OC(O)R^(d), —OC(S)R^(d),—C(O)R^(d), —C(S)R^(d), —C(O)OR^(d), —C(S)OR^(d), —S(O)R^(d),—S(O)₂R^(d), —C(O)NHR^(d), —C(S)NHR^(d), —C(O)NR^(d)R^(d),—C(S)NR^(d)R^(d), —S(O)₂NHR^(d), —S(O)₂NR^(d)R^(d), —C(NH)NHR^(d),—C(NH)NR^(d)R^(d), —NHC(O)R^(d), —NHC(S)R^(d), —NR^(d)C(O)R^(d),—NR^(d)C(S)R^(d), —NHS(O)₂R^(d), —NR^(d)S(O)₂R^(d), —NHC(O)NHR^(d),—NHC(S)NHR^(d), —NR^(d)C(O)NH₂, —NR^(d)C(S)NH₂, —NR^(d)C(O)NHR^(d),—NR^(d)C(S)NHR^(d), —NHC(O)NR^(d)R^(d), —NHC(S)NR^(d)R^(d),—NR^(d)C(O)NR^(d)R^(d), —NR^(d)C(S)NR^(d)R^(d), —NHS(O)₂NHR^(d),—NR^(d)S(O)₂NH₂, —NR^(d)S(O)₂NHR^(d), —NHS(O)₂NR^(d)R^(d),—NR^(d)S(O)₂NR^(d)R^(d), —NHR^(d), R^(f) or —NR^(d)R^(d), wherein eachR^(d) is independently selected from C₁₋₆ alkyl, arylalkyl, aryl,heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl or heterocycloalkylalkyl; and wherein the aromaticportion of R¹ is optionally substituted with from 1-3 substituentsindependently selected from R^(e), wherein R^(e) is selected from thegroup consisting of halogen, —CH═CH₂, —CN, —OH, —NH₂, —NO₂, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR′, —SR^(f), —OC(O)R^(f), —OC(S)R^(f),—C(O)R^(f), —C(S)R^(f), —C(O)OR^(f), —C(S)OR^(f), —S(O)R, —S(O)₂R^(f),—C(O)NHR^(f), —C(S)NHR^(f), —C(O)NR^(f)R^(f), —C(S)NR^(f)R^(f),—S(O)₂NHR^(f), —S(O)₂NR^(f)R^(f), —C(NH)NHR^(f), —C(NH)NR^(f)R^(f),—NHC(O)R^(f), —NHC(S)R^(f), —NR^(f)C(O)R^(f), —NR^(f)C(S)R^(f),—NHS(O)₂R^(f), —NR^(f)S(O)₂R^(f), —NHC(O)NHR^(f), —NHC(S)NHR^(f),—NR^(f)C(O)NH₂, —NR^(f)C(S)NH₂, —NR^(f)C(O)NHR^(f), —NR^(f)C(S)NHR^(f),—NHC(O)NR^(f)R^(f), —NHC(S)NR^(f)R^(f), —NR^(f)C(O)NR^(f)R^(f),—NR^(f)C(S)NR^(f)R^(f), —NHS(O)₂NHR^(f), —NR^(f)S(O)₂NH₂,—NR^(f)S(O)₂NHR^(f), —NHS(O)₂NR^(f)R^(f), —NR^(f)S(O)₂NR^(f)R^(f),—NHR^(f), —NR^(f)R^(f) and R^(f), wherein R^(f) is C₁₋₆alkyl or aryl; ortwo adjacent R¹ groups on the aryl or heteroaryl ring together with theatoms to which they are attached form a 5- or 6-membered ring havingfrom 0 to 2 additional heteroatoms selected from N, O or S, optionallysubstituted with from 1 to 3 R^(d) or R^(e) substituents. In someinstances, R^(f) is C₁₋₆alkyl. In other instances, R^(f) is aryl, suchas phenyl. All the other variables Y², Q, Z of formula (I) and R⁴, R⁵,R⁶, R⁷ and R⁸ are as defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is aryl orheteroaryl groups, wherein the heteroaryl group has from 1 to 4heteroatoms as ring members selected from N, O or S; and wherein thearyl or heteroaryl groups are optionally substituted with from 1 to 3 R¹substituents; or two adjacent R¹ groups on the phenyl or naphthyl ringtogether with the atoms to which they are attached form a 5- or6-membered ring having from 0 to 2 additional heteroatoms selected fromN, O or S, optionally substituted with from 1 to 3 R^(d) substituents.In other embodiments, Y¹ is CN, halogen, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆haloalkyl or C₁₋₆haloalkoxy. In some instances, Y¹ is phenyl,1-naphthyl or 2-naphthyl, each of which is optionally substituted withfrom one to three R¹. In other instances, Y¹ is phenyl, 1-naphthyl or2-naphthyl, each of which is optionally substituted with from one tothree R^(a). In other instances, Y¹ is phenyl, 1-naphthyl or 2-naphthyl,each of which is optionally substituted with from one to three R^(b). Inother instances, Y¹ is phenyl, 1-naphthyl or 2-naphthyl, each of whichis optionally substituted with from one to three R^(c). In otherinstances, Y¹ is phenyl, 1-naphthyl or 2-naphthyl, each of which isoptionally substituted with from one to three R^(d). In other instances,Y¹ is phenyl, 1-naphthyl or 2-naphthyl, each of which is optionallysubstituted with from one to three R^(e). In yet other instances, Y¹ isphenyl, 1-naphthyl or 2-naphthyl, each of which is optionallysubstituted with from one to three R^(a). In some instances, Y¹ isphenyl, 1-naphthyl or 2-naphthyl, is F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl or methylcarbamoyl. All the other variables Y²,Q, Z of formula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any ofthe embodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is1H-4-benzotriazolyl, 1H-5-benzotriazolyl, 1H-4-benzimidazolyl,1H-5-benzimidazolyl, 1H-4-indazolyl, 1H-5-indazolyl, 1H-6-indazolyl,1H-7-indazolyl, 1H-4-indolyl, 1H-5-indolyl, 1H-6-indolyl, 1H-7-indolyl,2-oxo-6-indolinyl, 2-oxo-4-indolinyl, 2-oxo-5-indolinyl,2-oxo-7-indolinyl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl,1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1,3-benzoxazol-4-yl,1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl,1,2-benzothiazol-4-yl, 1,2-benzothiazol-5-yl, 1,2-benzothiazol-6-yl,1,2-benzothiazol-7-yl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl,8-quinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl,8-isoquinolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl,5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl,5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl,4-indanyl, 5-indanyl, 5-tetralinyl, 6-tetralinyl,1,3-dihydroisobenzofuran-4-yl, 1,3-dihydroisobenzofuran-5-yl,2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl,2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl,1,3-dihydroisobenzothiophen-4-yl, 1,3-dihydroisobenzothiophen-5-yl,2,3-dihydrobenzothiophen-4-yl, 2,3-dihydrobenzothiophen-5-yl,2,3-dihydrobenzothiophen-6-yl, 2,3-dihydrobenzothiophen-7-yl,4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 5-isochromanyl,6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 5-chromanyl,6-chromanyl, 7-chromanyl, 8-chromanyl, 2,3-dihydro-1,3-benzothiazo-4-yl,2,3-dihydro-1,3-benzothiazo-5-yl, 2,3-dihydro-1,3-benzothiazo-6-yl,2,3-dihydro-1,3-benzothiazo-7-yl, 2,3-dihydro-1,2-benzothiazo-4-yl,2,3-dihydro-1,2-benzothiazo-5-yl, 2,3-dihydro-1,2-benzothiazo-6-yl,2,3-dihydro-1,2-benzothiazo-7-yl, 2,3-dihydro-1,3-benzoxazol-4-yl,2,3-dihydro-1,3-benzoxazol-5-yl, 2,3-dihydro-1,3-benzoxazol-6-yl,2,3-dihydro-1,3-benzoxazol-7-yl, 2,3-dihydro-1,2-benzoxazol-4-yl,2,3-dihydro-1,2-benzoxazol-5-yl, 2,3-dihydro-1,2-benzoxazol-6-yl,2,3-dihydro-1,2-benzoxazol-7-yl, 4-benzofuranyl, 5-benzofuranyl,6-benzofuranyl, 7-benzofuranyl, 4-benzothiophenyl, 5-benzothiophenyl,6-benzothiophenyl or 7-benzothiophenyl, each of which is optionallysubstituted with from 1 to 3 R¹ substituents; or 1 to 3R^(a)substituents; or 1 to 3 R^(b) substituents; or 1 to 3 R^(c)substituents; or 1 to 3 R^(d) substituents; or 1 to 3 R^(e)substituents;1 to 3 R^(f) substituents; or 1 to 3 substituents selected from F, Cl,Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl or methylcarbamoyl. All the other variables Y²,Q, Z of formula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any ofthe embodiments described herein.

In some embodiments, Y¹ is 5 or 6-membered heteroaryl, each of which isoptionally independently substituted with from 1-3 R¹ groups, whereinthe aromatic portion of R¹ is optionally substituted with from 1-3substituents independently selected from R^(e); or two adjacent R¹groups on the phenyl or naphthyl ring together with the atoms to whichthey are attached form a 5- or 6-membered ring having from 0 to 2additional heteroatoms selected from N, O or S, optionally substitutedwith from 1 to 3 R^(d) substituents. All the other variables Y², Q, Z offormula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is 5-pyrimidinyl,2-pyrimidinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrazinyl, 2-pyridazinyl, 3-pyridazinyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2-pyrazolyl,3-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-1-yl,1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl,1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl, 1-oxa-2,4-diazol-3-yl,1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1-oxa-2,5-diazol-4-yl,1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl, 1-thia-2,4-diazol-3-yl,1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl, 1-thia-2,5-diazol-4-yl,1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H-5-tetrazolyl, 2-furanyl,3-furanyl, 2-thiopenyl or 3-thiophenyl, each of which is optionallysubstituted with from 1 to 3 R¹ substituents; or 1 to 3 R^(a)substituents; or 1 to 3 R^(b) substituents; or 1 to 3 R^(c)substituents; or 1 to 3 R^(d) substituents; or 1 to 3 R^(e)substituents; 1 to 3 R^(f) substituents; or 1 to 3 substituents selectedfrom F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino, 1-hydroxy-1-methylethyl, methylcarbamoyl,1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy,4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl, piperazinyl,4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl,pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl. All the other variables Y², Q, Z offormula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of theembodiments described herein.

In certain embodiments of compounds of formula (I), Y¹ is selected fromthe group consisting of 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thiophenyl, 3-thiophenyl,2-amino-quinazolin-5-yl, 2-amino-quinazolin-6-yl,2-amino-quinazolin-6-yl, 2-amino-quinazolin-7-yl,2-amino-quinazolin-8-yl, 2-oxo-6-indolinyl, 2-oxo-4-indolinyl,2-oxo-5-indolinyl, 2-oxo-7-indolinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl and 1H-indazol-7-yl,each of which is substituted with from 1 to 2 susbtituents independentlyselected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O,C₂H₅O—, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl,5-methylamino-1,3,4-thiadiazol-2-yl, methylamino methylamino,dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. All the other variables Y², Q, Z of formula (I)and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of the embodimentsdescribed herein

In other embodiments of compounds of formula (I), Y¹ is1-benzotriazolyl, 1-benzimidazolyl, 1H-2-benzimidazolyl, 1-indazolyl,1H-3-indazolyl, 1-indolyl, 1H-2-indolyl, 1H-3-indolyl,1,2-benzoxazol-3-yl, 1,3-benzoxazol-2-yl, 1,2-benzothiazol-3-yl,1,3-benzothiazol-2-yl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 3-cinnolinyl,4-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl,2-benzofuranyl, 3-benzofuranyl, 2-benzothiophenyl or 3-benzothiophenyl,each of which is optionally substituted with from 1 to 3 R¹substituents; or 1 to 3 R^(a)substituents; or 1 to 3 R^(b) substituents;or 1 to 3 R^(c) substituents; or 1 to 3 R^(d) substituents; or 1 to 3R^(e)substituents; 1 to 3 R^(f) substituents; or 1 to 3 substituentsselected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O,—NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino, 1-hydroxy-1-methylethyl, methylcarbamoyl,1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy,4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl, piperazinyl,4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl,pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl. All the other variables Y², Q, Z offormula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is selected from:

each of which is optionally substituted with from 1 to 3 R¹substituents; or 1 to 3 R^(a) substituents; or 1 to 3 R^(b)substituents; or 1 to 3 R^(c) substituents; or 1 to 3 R^(d)substituents; or 1 to 3 R^(e) substituents; 1 to 3 R^(f) substituents;or 1 to 3 substituents selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino,1-hydroxy-1-methylethyl, methylcarbamoyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl, where the wavy line indicate thepoint of attachment to the rest of the molecule. The notation

means Y¹ can be attached to the rest of the molecule at any of theavailable positions of the Y¹ group set forth above. For example,

is meant to include 1-indolizinyl, 2-indolizinyl, 3-indolizinyl,4-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, and8-indolizinyl (i.e., substitutions can be at 1, 2, 3, 5, 6, 7 or 8positions of the indolizine ring).

In some embodiments of compounds of formula (I), Y¹ is selected from:

each of which is optionally substituted with from 1 to 3 R¹substituents; or 1 to 3 R^(a) substituents; or 1 to 3 R^(b)substituents; or 1 to 3 R^(c) substituents; or 1 to 3 R^(d)substituents; or 1 to 3 R^(e) substituents; 1 to 3 R^(f) substituents;or 1 to 3 substituents selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino,1-hydroxy-1-methylethyl, methylcarbamoyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl, where the wavy line indicates thepoint of attachment to the rest of the molecule. The notation

means Y¹ can be attached to the rest of the molecule at any of theavailable positions of the Y¹ group set forth above. For example,

is meant to include 1H-pyrrolo[3,2-b]pyridin-1-yl,1H-pyrrolo[3,2-b]pyridin-2-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl,1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl and1H-pyrrolo[3,2-b]pyridin-7-yl (i.e., substitutions can be at 1, 2, 3, 5,6, or 7 positions of the pyrrolo[3,2-b]pyridine ring). All the othervariables Y², Q, Z of formula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are asdefined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is selected from:

each of which is optionally substituted with from 1 to 3 R¹substituents; or 1 to 3 R^(a) substituents; or 1 to 3 R^(b)substituents; or 1 to 3 R^(c) substituents; or 1 to 3 R^(d)substituents; or 1 to 3 R^(e) substituents; 1 to 3 R^(f) substituents;or 1 to 3 substituents selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino,1-hydroxy-1-methylethyl, methylcarbamoyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl, where the wavy line indicates thepoint of attachment to the rest of the molecule. The notation

means Y¹ can be attached to the rest of the molecule at any of theavailable positions of the Y¹ group set forth above. For example,

is meant to include 5H-pyrrolo[3,2-c]pyridazin-3-yl,5H-pyrrolo[3,2-c]pyridazin-4-yl, 5H-pyrrolo[3,2-c]pyridazin-5-yl,5H-pyrrolo[3,2-c]pyridazin-6-yl, 5H-pyrrolo[3,2-c]pyridazin-7-yl (i.e.,substitutions can be at 3, 4, 5, 6, or 7 positions of the5H-pyrrolo[3,2-c]pyridazine ring). All the other variables Y², Q, Z offormula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is selected from:

each of which is optionally substituted with from 1 to 3 R¹substituents; or 1 to 3 R^(a) substituents; or 1 to 3 R^(b)substituents; or 1 to 3 R^(c) substituents; or 1 to 3 R^(d)substituents; or 1 to 3 R^(e) substituents; 1 to 3 R^(f) substituents;or 1 to 3 substituents selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino,1-hydroxy-1-methylethyl, methylcarbamoyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl, where the wavy line indicates thepoint of attachment to the rest of the molecule. The notation

means Y¹ can be attached to the rest of the molecule at any of theavailable positions of the Y¹ group set forth above. For example,

is meant to include 5H-pyrrolo[3,2-c]pyrimidin-2-yl,5H-pyrrolo[3,2-c]pyrimidin-4-yl, 5H-pyrrolo[3,2-c]pyrimidin-5-yl,5H-pyrrolo[3,2-c]pyrimidin-6-yl and 5H-pyrrolo[3,2-c]pyrimidin-7-yl(i.e., substitutions can be at 2, 4, 5, 6, or 7 positions of the5H-pyrrolo[3,2-c]pyrimidine ring). All the other variables Y², Q, Z offormula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is selected from:

each of which is optionally substituted with from 1 to 3 R¹substituents; or 1 to 3 R^(a) substituents; or 1 to 3 R^(b)substituents; or 1 to 3 R^(c) substituents; or 1 to 3 R^(d)substituents; or 1 to 3 R^(e) substituents; 1 to 3 R^(f) substituents;or 1 to 3 substituents selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino,1-hydroxy-1-methylethyl, methylcarbamoyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl, where the wavy line indicates thepoint of attachment to the rest of the molecule. The notation

means Y¹ can be attached to the rest of the molecule at any of theavailable positions of the Y¹ group set forth above. For example,

is meant to include 5H-pyrrolo[2,3-b]pyrazin-2-yl,5H-pyrrolo[2,3-b]pyrazin-3-yl, 5H-pyrrolo[2,3-b]pyrazin-5-yl,5H-pyrrolo[2,3-b]pyrazin-6-yl, 5H-pyrrolo[2,3-b]pyrazin-7-yl, (i.e.,substitutions can be at 2, 3, 5, 6, or 7 positions of the5H-pyrrolo[2,3-b]pyrazine ring). All the other variables Y², Q, Z offormula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), Y¹ is CN, halogen, —OH,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted C₁₋₆haloalkyl, or optionally substitutedC₁₋₆haloalkoxy. In other embodiments, Y¹ is CN, halogen, —OH, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl or C₁₋₆haloalkoxy, each of which isoptionally substituted with from 1 to 3 R¹ substituents; or 1 to 3 R^(a)substituents; or 1 to 3 R^(b) substituents; or 1 to 3 R^(c)substituents; or 1 to 3 R^(d) substituents; or 1 to 3 R^(e)substituents; 1 to 3 R^(f) substituents; or 1 to 3 substituents selectedfrom F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido ormethylcarbamoyl. In some embodiments, Y¹ is CN, halogen, —OH, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl or C₁₋₆haloalkoxy. In otherembodiments, Y¹ is CN, Cl, Br, F, I, —OH, —OCH₃, —CF₃, or —OCF₃, each ofwhich is optionally substituted with from 1 to 3 R¹ substituents; or 1to 3 R^(a) substituents; or 1 to 3 R^(b) substituents; or 1 to 3 R^(c)substituents; or 1 to 3 R^(d) substituents; or 1 to 3 R^(e)substituents;1 to 3 R^(f) substituents; or 1 to 3 substituents selected from F, Cl,Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino,1-hydroxy-1-methylethyl, methylcarbamoyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl, In other embodiments, Y¹ is CN,halogen, —OH, CH₃, CH₃O—, CF₃, CF₃O, cyclopropyl or cyclopropylmethyl.All the other variables Y², Q, Z of formula (I) and R⁴, R⁵, R⁶, R⁷ andR⁸ are as defined in any of the embodiments described herein.

In any of embodiments of compounds of formula (I) above and describedherein, where appropriate, each R¹ is independently selected fromhalogen, —CN, —OH, —CF₃, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₆cycloalkoxy,—NO₂, benzyl, phenyl, cyclopropyl, cyclopropylmethyl,1-cycanocyclopropyl, 1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy,C₁₋₆alkyl-1,2,4-oxadiazol-3-yl, 5-C₁₋₆alkyl-1,3,4-oxadiazol-2yl,5-di(C₁₋₆alkyl)amino-1,3,4-oxadiazol-2yl,5-C₁₋₆alkylamino-1,3,4-thiadiazol-2-yl, cyclobutyl, cyclobutylmethyl,cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl,—OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b), —NHC(O)R^(b), —C(O)NHR^(b),—NHR^(b) or —NR^(b)R^(b). In certain instances, R¹ is F, Cl, Br, I, —CN,—OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, C₂H₅O—, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, 1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy,4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl, piperazinyl,4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl,pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl,1,3,4-thiadiazol-2-yl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl,1-pyrrolidinyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl.

In some embodiments of compounds of formula (I), Y¹ is selected from thegroup consisting of 5-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl,2-methoxy-5-pyrimidinyl, 2-methoxy-3-pyrimidinyl,2-methoxy-4-pyrimidinyl, 4-methoxy-2-pyrimidinyl,4-methoxy-4-pyrimidinyl, 4-methoxy-5-pyrimidinyl,5-methoxy-2-pyrimidinyl, 5-methoxy-4-pyrimidinyl,2-cyclopropyl-5-pyrimidinyl, 2-cyclopropyl-3-pyrimidinyl,2-cyclopropyl-4-pyrimidinyl, 4-cyclopropyl-2-pyrimidinyl,4-cyclopropyl-4-pyrimidinyl, 4-cyclopropyl-5-pyrimidinyl,5-cyclopropyl-2-pyrimidinyl, 5-cyclopropyl-4-pyrimidinyl,2-cyclopropylmethyl-5-pyrimidinyl, 2-cyclopropylmethyl-3-pyrimidinyl,2-cyclopropylmethyl-4-pyrimidinyl, 4-cyclopropylmethyl-2-pyrimidinyl,4-cyclopropylmethyl-4-pyrimidinyl, 4-cyclopropylmethyl-5-pyrimidinyl,5-cyclopropylmethyl-2-pyrimidinyl, 5-cyclopropylmethyl-4-pyrimidinyl,2-methyl-5-pyrimidinyl, 2-methyl-3-pyrimidinyl, 2-methyl-4-pyrimidinyl,4-methyl-2-pyrimidinyl, 4-methyl-4-pyrimidinyl, 4-methyl-5-pyrimidinyl,5-methyl-2-pyrimidinyl, 5-methyl-4-pyrimidinyl, 2-halo-5-pyrimidinyl,2-halo-3-pyrimidinyl, 2-halo-4-pyrimidinyl, 4-halo-2-pyrimidinyl,4-halo-4-pyrimidinyl, 4-halo-5-pyrimidinyl, 5-halo-2-pyrimidinyl,5-halo-4-pyrimidinyl, 2-(1-cyanocyclopropyl)-5-pyrimidinyl,2-(1-cyanocyclopropyl)-3-pyrimidinyl,2-(1-cyanocyclopropyl)-4-pyrimidinyl,4-(1-cyanocyclopropyl)-2-pyrimidinyl,4-(1-cyanocyclopropyl)-4-pyrimidinyl,4-(1-cyanocyclopropyl)-5-pyrimidinyl,5-(1-cyanocyclopropyl)-2-pyrimidinyl,5-(1-cyanocyclopropyl)-4-pyrimidinyl, 2-cyclopropylamino-5-pyrimidinyl,2-cyclopropylamino-3-pyrimidinyl, 2-cyclopropylamino-4-pyrimidinyl,4-cyclopropylamino-2-pyrimidinyl, 4-cyclopropylamino-4-pyrimidinyl,4-cyclopropylamino-5-pyrimidinyl, 5-cyclopropylamino-2-pyrimidinyl,5-cyclopropylamino-4-pyrimidinyl, 2-dimethylamino-5-pyrimidinyl,2-dimethylamino-3-pyrimidinyl, 2-dimethylamino-4-pyrimidinyl,4-dimethylamino-2-pyrimidinyl, 4-dimethylamino-4-pyrimidinyl,4-dimethylamino-5-pyrimidinyl, 5-dimethylamino-2-pyrimidinyl,5-dimethylamino-4-pyrimidinyl, 2-cyano-5-pyrimidinyl,2-cyano-3-pyrimidinyl, 2-cyano-4-pyrimidinyl, 4-cyano-2-pyrimidinyl,4-cyano-4-pyrimidinyl, 4-cyano-5-pyrimidinyl, 5-cyano-2-pyrimidinyl,5-cyano-4-pyrimidinyl, 2-trifluoromethyl-5-pyrimidinyl,2-trifluoromethyl-3-pyrimidinyl, 2-trifluoromethyl-4-pyrimidinyl,4-trifluoromethyl-2-pyrimidinyl, 4-trifluoromethyl-4-pyrimidinyl,4-trifluoromethyl-5-pyrimidinyl, 5-trifluoromethyl-2-pyrimidinyl,5-trifluoromethyl-4-pyrimidinyl, 2-trifluoromethoxy-5-pyrimidinyl,2-trifluoromethoxy-3-pyrimidinyl, 2-trifluoromethoxy-4-pyrimidinyl,4-trifluoromethoxy-2-pyrimidinyl, 4-trifluoromethoxy-4-pyrimidinyl,4-trifluoromethoxy-5-pyrimidinyl, 5-trifluoromethoxy-2-pyrimidinyl,5-trifluoromethoxy-4-pyrimidinyl, 2-hydroxy-5-pyrimidinyl,2-hydroxy-3-pyrimidinyl, 2-hydroxy-4-pyrimidinyl,4-hydroxy-2-pyrimidinyl, 4-hydroxy-4-pyrimidinyl,4-hydroxy-5-pyrimidinyl, 5-hydroxy-2-pyrimidinyl,5-hydroxy-4-pyrimidinyl, 2-amino-5-pyrimidinyl, 2-amino-3-pyrimidinyl,2-amino-4-pyrimidinyl, 4-amino-2-pyrimidinyl, 4-amino-4-pyrimidinyl,4-amino-5-pyrimidinyl, 5-amino-2-pyrimidinyl, 5-amino-4-pyrimidinyl,2-methylamino-5-pyrimidinyl, 2-methylamino-3-pyrimidinyl,2-methylamino-4-pyrimidinyl, 4-methylamino-2-pyrimidinyl,4-methylamino-4-pyrimidinyl, 4-methylamino-5-pyrimidinyl,5-methylamino-2-pyrimidinyl, 5-methylamino-4-pyrimidinyl,2-dimethylamino-5-pyrimidinyl, 2-dimethylamino-3-pyrimidinyl,2-dimethylamino-4-pyrimidinyl, 4-dimethylamino-2-pyrimidinyl,4-dimethylamino-4-pyrimidinyl, 4-dimethylamino-5-pyrimidinyl,5-dimethylamino-2-pyrimidinyl, 5-dimethylamino-4-pyrimidinyl,2-acetamido-5-pyrimidinyl, 2-acetamido-3-pyrimidinyl,2-acetamido-4-pyrimidinyl, 4-acetamido-2-pyrimidinyl,4-acetamido-4-pyrimidinyl, 4-acetamido-5-pyrimidinyl,5-acetamido-2-pyrimidinyl, 5-acetamido-4-pyrimidinyl,2-methylthio-5-pyrimidinyl, 2-methylthio-3-pyrimidinyl,2-methylthio-4-pyrimidinyl, 4-methylthio-2-pyrimidinyl,4-methylthio-4-pyrimidinyl, 4-methylthio-5-pyrimidinyl,5-methylthio-2-pyrimidinyl, 5-methylthio-4-pyrimidinyl,2-acetoxy-5-pyrimidinyl, 2-acetoxy-3-pyrimidinyl,2-acetoxy-4-pyrimidinyl, 4-acetoxy-2-pyrimidinyl,4-acetoxy-4-pyrimidinyl, 4-acetoxy-5-pyrimidinyl,5-acetoxy-2-pyrimidinyl, 5-acetoxy-4-pyrimidinyl,2-acetyl-5-pyrimidinyl, 2-acetyl-3-pyrimidinyl, 2-acetyl-4-pyrimidinyl,4-acetyl-2-pyrimidinyl, 4-acetyl-4-pyrimidinyl, 4-acetyl-5-pyrimidinyl,5-acetyl-2-pyrimidinyl, 5-acetyl-4-pyrimidinyl,2-methoxycarbonyl-5-pyrimidinyl, 2-methoxycarbonyl-3-pyrimidinyl,2-methoxycarbonyl-4-pyrimidinyl, 4-methoxycarbonyl-2-pyrimidinyl,4-methoxycarbonyl-4-pyrimidinyl, 4-methoxycarbonyl-5-pyrimidinyl,5-methoxycarbonyl-2-pyrimidinyl, 5-methoxycarbonyl-4-pyrimidinyl,2-methylcarbamoyl-5-pyrimidinyl, 2-methylcarbamoyl-3-pyrimidinyl,2-methylcarbamoyl-4-pyrimidinyl, 4-methylcarbamoyl-2-pyrimidinyl,4-methylcarbamoyl-4-pyrimidinyl, 4-methylcarbamoyl-5-pyrimidinyl,5-methylcarbamoyl-2-pyrimidinyl, 5-methylcarbamoyl-4-pyrimidinyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 3-methoxy-2-pyridyl,4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl, 6-methoxy-2-pyridyl,2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 5-methoxy-3-pyridyl,6-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 3-methoxy-4-pyridyl,3-halo-2-pyridyl, 4-halo-2-pyridyl, 5-halo-2-pyridyl, 6-halo-2-pyridyl,2-halo-3-pyridyl, 4-halo-3-pyridyl, 5-halo-3-pyridyl, 6-halo-3-pyridyl,2-halo-4-pyridyl, 3-halo-4-pyridyl, 3-cyano-2-pyridyl,4-cyano-2-pyridyl, 5-cyano-2-pyridyl, 6-cyano-2-pyridyl,2-cyano-3-pyridyl, 4-cyano-3-pyridyl, 5-cyano-3-pyridyl,6-cyano-3-pyridyl, 2-cyano-4-pyridyl, 3-cyano-4-pyridyl,3-hydroxy-2-pyridyl, 4-hydroxy-2-pyridyl, 5-hydroxy-2-pyridyl,6-hydroxy-2-pyridyl, 2-hydroxy-3-pyridyl, 4-hydroxy-3-pyridyl,5-hydroxy-3-pyridyl, 6-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl,3-hydroxy-4-pyridyl, 3-trifluoromethyl-2-pyridyl,4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl,6-trifluoromethyl-2-pyridyl, 2-trifluoromethyl-3-pyridyl,4-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl,6-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl,3-trifluoromethyl-4-pyridyl, 3-amino-2-pyridyl, 4-amino-2-pyridyl,5-amino-2-pyridyl, 6-amino-2-pyridyl, 2-amino-3-pyridyl,4-amino-3-pyridyl, 5-amino-3-pyridyl, 6-amino-3-pyridyl,2-amino-4-pyridyl, 3-amino-4-pyridyl, 3-trifluoromethoxy-2-pyridyl,4-trifluoromethoxy-2-pyridyl, 5-trifluoromethoxy-2-pyridyl,6-trifluoromethoxy-2-pyridyl, 2-trifluoromethoxy-3-pyridyl,4-trifluoromethoxy-3-pyridyl, 5-trifluoromethoxy-3-pyridyl,6-trifluoromethoxy-3-pyridyl, 2-trifluoromethoxy-4-pyridyl,3-trifluoromethoxy-4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl,5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-methyl-3-pyridyl,4-methyl-3-pyridyl, 5-methyl-3-pyridyl, 6-methyl-3-pyridyl,2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 3-methoxy-2-pyridyl,4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl, 6-methoxy-2-pyridyl,2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 5-methoxy-3-pyridyl,6-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 3-methoxy-4-pyridyl,3-cyclopropyl-2-pyridyl, 4-cyclopropyl-2-pyridyl,5-cyclopropyl-2-pyridyl, 6-cyclopropyl-2-pyridyl,2-cyclopropyl-3-pyridyl, 4-cyclopropyl-3-pyridyl,5-cyclopropyl-3-pyridyl, 6-cyclopropyl-3-pyridyl,2-cyclopropyl-4-pyridyl, 3-cyclopropyl-4-pyridyl,3-cyclopropylmethyl-2-pyridyl, 4-cyclopropylmethyl-2-pyridyl,5-cyclopropylmethyl-2-pyridyl, 6-cyclopropylmethyl-2-pyridyl,2-cyclopropylmethyl-3-pyridyl, 4-cyclopropylmethyl-3-pyridyl,5-cyclopropylmethyl-3-pyridyl, 6-cyclopropylmethyl-3-pyridyl,2-cyclopropylmethyl-4-pyridyl, 3-cyclopropylmethyl-4-pyridyl,3-cyclopropylamino-2-pyridyl, 4-cyclopropylamino-2-pyridyl,5-cyclopropylamino2-pyridyl, 6-cyclopropylamino-2-pyridyl,2-cyclopropylamino-3-pyridyl, 4-cyclopropylamino-3-pyridyl,5-cyclopropylamino-3-pyridyl, 6-cyclopropylamino-3-pyridyl,2-cyclopropylamino-4-pyridyl, 3-cyclopropylamino-4-pyridyl,3-cyclopropylmethylamino-2-pyridyl, 4-cyclopropylmethylamino-2-pyridyl,5-cyclopropylmethylamino-2-pyridyl, 6-cyclopropylmethylamino-2-pyridyl,2-cyclopropylmethylamino-3-pyridyl, 4-cyclopropylmethylamino-3-pyridyl,5-cyclopropylmethylamino-3-pyridyl, 6-cyclopropylmethylamino-3-pyridyl,2-cyclopropylmethylamino-4-pyridyl, 3-cyclopropylmethylamino-4-pyridyl,3-methylamino-2-pyridyl, 4-methylamino-2-pyridyl,5-methylamino-2-pyridyl, 6-methylamino-2-pyridyl,2-methylamino-3-pyridyl, 4-methylamino-3-pyridyl,5-methylamino-3-pyridyl, 6-methylamino-3-pyridyl,2-methylamino-4-pyridyl, 3-methylamino-4-pyridyl,3-dimethylamino-2-pyridyl, 4-dimethylamino-2-pyridyl,5-dimethylamino-2-pyridyl, 6-dimethylamino-2-pyridyl,2-dimethylamino-3-pyridyl, 4-dimethylamino-3-pyridyl,5-dimethylamino-3-pyridyl, 6-dimethylamino-3-pyridyl,2-dimethylamino-4-pyridyl, 3-dimethylamino-4-pyridyl,3-methylthio-2-pyridyl, 4-methylthio-2-pyridyl, 5-methylthio-2-pyridyl,6-methylthio-2-pyridyl, 2-methylthio-3-pyridyl, 4-methylthio-3-pyridyl,5-methylthio-3-pyridyl, 6-methylthio-3-pyridyl, 2-methylthio-4-pyridyl,3-methylthio-4-pyridyl, 3-acetoxy-2-pyridyl, 4-acetoxy-2-pyridyl,5-acetoxy-2-pyridyl, 6-acetoxy-2-pyridyl, 2-acetoxy-pyridyl,4-acetoxy-3-pyridyl, 5-acetoxy-3-pyridyl, 6-acetoxy-3-pyridyl,2-acetoxy-4-pyridyl, 3-acetoxy-4-pyridyl, 3-acetyl-2-pyridyl,4-acetyl-2-pyridyl, 5-acetyl-2-pyridyl, 6-acetyl-2-pyridyl,2-acetyl-pyridyl, 4-acetyl-3-pyridyl, 5-acetyl-3-pyridyl,6-acetyl-3-pyridyl, 2-acetyl-4-pyridyl, 3-acetyl-4-pyridyl,3-methoxycarbonyl-2-pyridyl, 4-methoxycarbonyl-2-pyridyl,5-methoxycarbonyl-2-pyridyl, 6-methoxycarbonyl-2-pyridyl,2-methoxycarbonyl-3-pyridyl, 4-methoxycarbonyl-3-pyridyl,5-methoxycarbonyl-3-pyridyl, 6-methoxycarbonyl-3-pyridyl,2-methoxycarbonyl-4-pyridyl, 3-methoxycarbonyl-4-pyridyl,3-methylcarbamoyl-2-pyridyl, 4-methylcarbamoyl-2-pyridyl,5-methylcarbamoyl-2-pyridyl, 6-methylcarbamoyl-2-pyridyl,2-methylcarbamoyl-3-pyridyl, 4-methylcarbamoyl-3-pyridyl,5-methylcarbamoyl-3-pyridyl, 6-methylcarbamoyl-3-pyridyl,2-methylcarbamoyl-4-pyridyl, 3-methylcarbamoyl-4-pyridyl,3-acetamido-2-pyridyl, 4-acetamido-2-pyridyl, 5-acetamido-2-pyridyl,6-acetamido-2-pyridyl, 2-acetamido-3-pyridyl, 4-acetamido-3-pyridyl,5-acetamido-3-pyridyl, 6-acetamido-3-pyridyl, 2-acetamido-4-pyridyl and3-acetamido-4-pyridyl, 3-(1-cyanocyclopropyl)-2-pyridyl,4-(1-cyanocyclopropyl)-2-pyridyl, 5-(1-cyanocyclopropyl)-2-pyridyl,6-(1-cyanocyclopropyl)-2-pyridyl, 2-(1-cyanocyclopropyl)-3-pyridyl,4-(1-cyanocyclopropyl)-3-pyridyl, 5-(1-cyanocyclopropyl)-3-pyridyl,6-(1-cyanocyclopropyl)-3-pyridyl, 2-(1-cyanocyclopropyl)-4-pyridyl,3-(1-cyanocyclopropyl)-4-pyridyl, each of which is optionallysubstituted with from 1, 2, or 3 susbtituents independently selectedfrom F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂,cyclopropyl, 1-cyanocyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl,1-pyrrolidinyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. In some instances, the 1, 2, 3 substituents areon the aromatic portion of Y¹. In other instances, the 1, 2, 3substituents are on the aliphatic portion of Y¹. All the other variablesY², Q, Z of formula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in anyof the embodiments described herein.

In certain embodiments of compounds of formula (I), Y¹ is phenylsubstituted with from 1 to 2 susbtituents independently selected from F,Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, C₂H₅O—, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, 1-carboxycyclopropyl,1-carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl,1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,cycloheyloxy, 4-morpholino, 4-hydroxypiperidinyl, 1-piperidinyl,piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl,5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2yl,5-dimethylamino-1,3,4-oxadiazol-2yl,5-methylamino-1,3,4-thiadiazol-2-yl, methylamino methylamino,dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl.

In other embodiments of compounds of formula (I), Y¹ is selected fromthe group consisting of phenyl, 2-halophenyl, 3-halophenyl,4-halophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-aminophenyl,3-aminophenyl, 4-aminophenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-cyclopropylphenyl, 3-cyclopropylphenyl,4-cyclopropylphenyl, 2-cyclopropylmethylphenyl,3-cyclopropylmethylphenyl, 4-cyclopropylmethylphenyl,2-cyclopropylmethylaminophenyl, 3-cyclopropylmethylaminophenyl,4-cyclopropylmethylaminophenyl, 2-cyclopropylaminophenyl,3-cyclopropylaminophenyl, 4-cyclopropylaminophenyl, 2-methylaminophenyl,3-methylaminophenyl, 4-methylaminophenyl, 2-dimethylaminophenyl,3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl, 2-acetoxyphenyl,3-acetoxyphenyl, 4-acetoxyphenyl, 2-acetylphenyl, 3-acetylphenyl,4-acetylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl,4-methoxycarbonylphenyl, 2-acetamidophenyl, 3-acetamidophenyl,4-acetamidophenyl, 2-methylcarbamoylphenyl, 3-methylcarbamoylphenyl,4-methylcarbamoylphenyl, 2-(1-cyanocyclopropyl)phenyl,3-(1-cyanocyclopropyl)phenyl and 4-(1-cyanocyclopropyl)phenyl, each ofwhich is optionally substituted with from 1, 2 or susbtituentsindependently selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—,CH₃—, CH₃O, —NO₂, cyclopropyl, 1-cyanocyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino or 1-hydroxy-1-methylethyl or methylcarbamoyl.In some instances, the 1, 2, 3 substituents are on the aromatic portionof Y¹. In other instances, the 1, 2, 3 substituents are on the aliphaticportion of Y¹. All the other variables Y², Q, Z of formula (I) and R⁴,R⁵, R⁶, R⁷ and R⁸ are as defined in any of the embodiments describedherein.

In some embodiments of compounds of formula (I), Y² is as defined in thesummary of the invention and the other variables Y¹, Q and Z of formula(I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of the aboveembodiments and any of the embodiments described herein.

In some embodiments of compounds of formula (I), Y² is H, halogen, CN,C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₆cycloalkylamino,C₃₋₆cycloalkyl-C₁₋₃alkylamino, aryl, heteroaryl, arylalkyl orheteroarylalkyl, wherein the aliphatic or aromatic portion of Y² isoptionally substituted with 1, 2 or 3 substituents independentlyselected from H, F, Cl, I, CN, CH₃, CH₃O—, phenyl, CF₃ or CF₃O. Incertain instances, Y² is H, halogen, CN, C₁₋₆alkyl, C₁₋₆alkoxy,C₃₋₆cycloalkylamino or C₃₋₆cycloalkyl-C₁₋₃alkylamino, wherein thealiphatic portion of Y² is optionally substituted with 1, 2 or 3substituents independently selected from H, F, Cl, I, CN, CH₃, CH₃O—,phenyl, CF₃ or CF₃O. All other variables Y¹, Q and Z of formula (I) andR⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of the embodiments describedherein.

In some embodiments of compounds of formula (I), Y² is H, F, Cl, I, CN,CH₃, CH₃O—, cyclopropylamino or cyclopropylmethylamino. All the othervariables Y¹, Q and Z of formula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are asdefined in any of the embodiments described herein.

In some preferred embodiments of compounds of formula (I), Y² is H andall the other variables Y¹, Q and Z of formula (I) and R⁴, R⁵, R⁶, R⁷and R⁸ are as defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), Q is selected from H,F, Cl or CH₃. In one embodiment, Q is H. In another embodiment, Q is F.In yet another embodiment, Q is CH₃. In still other embodiment, Q is Cl.In another embodiment, Q is H or F. All the other variables Y¹, Y², Z offormula (I) and R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), Z is as defined in thesummary of invention. All the other variables of formula (I) and R⁴, R⁵,R⁶, R⁷ and R⁸ are as defined in any of the embodiments described herein.

In some embodiments of compounds of formula (I), Z is —N(R⁴)(R⁵) or—C(R⁶)(R⁷)(R⁸), wherein R⁴ and R⁵ are each independently selected fromthe group consisting of H, optionally substituted C₁₋₆alkyl, optionallysubstituted C₃₋₈cycloalkyl, optionally substituted C₃₋₈cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl; or R⁴ and R⁵ taken together with thenitrogen atom to which they are attached form a four to eight-memberedring having from 0-2 additional heteroatoms as ring members selectedfrom N, O or S, wherein the four to eight-membered ring is optionallysubstituted with from one to three groups independently selected fromC₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl or R^(e). R⁶, R⁷ and R⁸ are eachindependently H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₈cycloalkyl, C₃₋₈ cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl or —X²R⁹; wherein thealiphatic or aromatic portion of R⁶, R⁷ and R⁸ are each optionallysubstituted with from 1 to 3 members independently selected from thegroup consisting of C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl,arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,heteroarylalkyl and R^(e); or any two of the R⁶, R⁷ and R⁸ groups takentogether with the carbon atom to which they are attached form a 3 to8-membered carbocyclic ring or a 4 to 8-membered heterocyclic ringhaving from 1 to 2 heteroatoms as ring members selected from N, O or S,wherein the 3 to 8-membered carbocyclic ring or the 4 to 8-memberedheterocyclic ring is optionally substituted with from one to threegroups independently selected from C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl or R^(e), provided at each occurrence, atleast two of the R⁶, R⁷ and R⁸ groups are not simultaneously hydrogen.All the other variables Y¹, Y² and Q of formula (I) are as defined inany of the embodiments described herein.

In some embodiments of compounds of formula (I), Z is —N(R⁴)(R⁵),wherein R⁴ and R⁵ are each independently selected from C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl orheteroaryl-C₁₋₄alkyl, each of which is optionally substituted with from(i) 1-3 substituents independently selected from C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆-haloalkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl orR^(e); or (ii) 1, 2 or 3 R^(a) substituents; or (iii) 1, 2 or 3 R^(b)substituents; or (iv) 1, 2 or 3 R^(c) substituents; or (v) 1, 2 or 3R^(d) substituents; or (vi) 1, 2 or 3 R^(f) groups. All the othervariables Y¹, Y² and Q of formula (I) are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), R⁴ is —CH₃ and R⁵ isC₂₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl,heteroaryl or heteroaryl-C₁₋₄alkyl, each of which is optionallysubstituted with from (i) 1-3 substituents independently selected fromC₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl orR^(e); or (ii) 1, 2 or 3 R^(a) substituents; or (iii) 1, 2 or 3 R^(b)substituents; or (iv) 1, 2 or 3 R^(c) substituents; or (v) 1, 2 or 3R^(d) substituents; or (vi) 1, 2 or 3 R^(f) groups. In certaininstances, R⁴ is —CH₃ and R⁵ is C₂₋₆alkyl. All the other variables Y¹,Y² and Q of formula (I) are as defined in any of the embodimentsdescribed herein.

In some embodiments of compounds of formula (I), R⁴ and R⁵ are eachindependently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl orheteroaryl-C₁₋₄alkyl, each of which is optionally substituted with from1, 2 or 3 R^(b) members selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In certain instances,R^(x) is F, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. All the other variablesY¹, Y² and Q of formula (I) are as defined in any of the embodimentsdescribed herein.

In some embodiments of compounds of formula (I), R⁴ is —CH₃ and R⁵ isC₂₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, aryl-C₁₋₄alkyl,heteroaryl or heteroaryl-C₁₋₄alkyl, each of which is optionallysubstituted with from 1, 2 or 3 R^(x) members selected from F, Cl, Br,I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In certain instances,R^(x) is F, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. All the other variablesY¹, Y² and Q of formula (I) are as defined in any of the embodimentsdescribed herein.

In some embodiments of compounds of formula (I), R⁴ is —CH₃ and R⁵ isselected from ethyl, propyl, butyl, pentyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl,cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl, eachof which is optionally substituted with from 1-3 substituentsindependently selected from F, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O,—NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. All the other variablesY¹, Y² and Q of formula (I) are as defined in any of the embodimentsdescribed herein.

In some embodiments of compounds of formula (I), Z is —N(R⁴)(R⁵),wherein —N(R⁴)(R⁵) is selected from 1-azetindinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl, 3-oxazolidinyl,3-thiazolidinyl, 2-isoxazolidinyl, 2-isothiazolidinyl, 1-pyrazolidinyl,1-piperazinyl, 1-hexahydropyrimidinyl or 1-hexahydropyridazinyl, each ofwhich is (i) optionally substituted with from 1 to 3 R²⁶ substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl and R^(c); or (ii) two adjacentR²⁶ substituents together with the atom to which they are attached forma 5 or 6-membered aromatic ring having from 0 to 2 additional atoms asring members selected from O, N or S or (iii) optionally substitutedwith from 1 to 8 deuteriums with at least 52.5%, 60%, 70%, 75%, 80%,90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for eachdeuterium. In certain instances, R²⁶ is F, Cl, Br, I, —CN, —OH, —CF₃,NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In other instances, R²⁶is F, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In other instances, R²⁶is F, CH₃, methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—, vinyl,propen-3-yl or CH₃(CO)(CH₃)N—. In some embodiments, each hydrogen atomin Z is optionally replaced by a deuterium atom with at least 52.5%,60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuteriumincorporation for each deuterium. All the other variables Y¹, Y² and Qof formula (I) are as defined in any of the embodiments describedherein.

In some embodiments of compounds of formula (I), Z is —C(R⁶)(R⁷)(R⁸),where R⁶ is H and R⁷ and R⁸ are each independently C₁₋₆alkyl, optionallysubstituted with from 1 to 3 R^(d) or R^(e). In some embodiments, R⁶, R⁷and R⁸ are each independently C₁₋₆alkyl, optionally substituted withfrom 1 to 3 R^(d) or R^(e). In some embodiments, —C(R⁶)(R⁷)(R⁸) iscyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cycloheptyl,cyclooctyl, each of which is optionally substituted with from 1-3 R²⁸substituents independently selected from F, Cl, Br, I, —CN, —OH, —CF₃,NH₂, CF₃O—, CH₃—, CH₃O, —CH₂CH═CH₂, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, vinyl, methylamino, dimethylamino, methylthio,acetoxy, acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In some instances, R²⁸ isF, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In some embodiments,—C(R⁶)(R⁷)(R⁸) is 2-azetindinyl, 3-azetindinyl, 3-pyrrolidinyl,2-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-morpholinyl, 3-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl,2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl,4-thiazolidinyl, 5-thiazolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl,5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl,5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 2-piperazinyl,2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl,3-hexahydropyridazinyl or 4-hexahydropyridazinyl, each of which isoptionally substituted with 1 to 3 R²⁸ substituents. In someembodiments, each hydrogen atom in Z is optionally replaced by adeuterium atom with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%,99.5% or 99.9% deuterium incorporation for each deuterium. All the othervariables Y¹, Y² and Q of formula (I) are as defined in any of theembodiments described herein.

In some embodiments of compounds of formula (I), Z is selected from thegroup consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cycloheptyl, cyclooctyl, 1-azetindinyl, 1-pyrrolidinyl, 1-piperidinyl,4-morpholinyl, 4-thiomorpholinyl 3-oxazolidinyl, 3-thiazolidinyl,2-isoxazolidinyl, 2-isothiazolidinyl, 1-pyrazolidinyl, 1-piperazinyl,1-hexahydropyrimidinyl, 1-hexahydropyridazinyl, (CH₃)(CF₃CH₂)N—,cycloproyplmethylamino, sec-butyl, pentan-2-yl and pentan-3-yl, each ofwhich is (i) optionally substituted with from one to three R²⁷substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆-haloalkyl, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl andR^(c); or (ii) two adjacent R²⁷ substituents together with the atom towhich they are attached form a 5 or 6-membered aromatic ring having from0 to 2 additional atoms as ring members selected from O, N or S; or(iii) optionally substituted with from 1 to 11 deuteriums having atleast 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuteriumincorporation for each deuterium. In one embodiment, Z is cyclopropyloptionally substituted with 1 to 2 R²⁷ groups. In another embodiment, Zis cyclopentyl optionally substituted with 1 to 2 R²⁷ groups. In yetanother embodiment Z is 1-pyrrolidinyl optionally substituted with 1 to2 R²⁷ groups. In other embodiment, Z is 1-piperidinyl optionallysubstituted with 1 to 2 R²⁷ groups. In another embodiment, Z is1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, (3S)-3-fluoro-1-pyrrolidinyl,(3R)-3-fluoro-1-pyrrolidinyl, 3,3-difluoro-1-pyrrolidinyl,3-C₁₋₆alkyl-C(O)—C₁₋₆alkyl-N-1-pyrrolidinyl,3-C₁₋₆alkyl-C(O)NH-1-pyrrolidinyl, C₁₋₆alkoxycarbonyl-1-pyrrolidinyl or3,3-dimethyl-1-pyrrolidinyl. In certain instances, R²⁷ is F, Cl, Br, I,—CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In one instance, R²⁷ is—F, methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—, vinyl,propen-3-yl or CH₃(CO)(CH₃)N—. In another instance, R²⁷ is —F,methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH— or CH₃(CO)(CH₃)N—. Inyet another instance, R²⁷ is vinyl or propen-3-yl. All the othervariables Y¹, Y² and Q of formula (I) are as defined in any of theembodiments described herein.

Subformulae of Formula I

In one embodiment of the invention, compounds of formula (I) havesubformula (Ia):

where the substituents Y¹, Y², Q, R⁴ and R⁵ are as defined in any of theembodiments disclosed herein. In some embodiments, R⁴ is CH₃ and R⁵ isC₂₋₆alkyl optionally substituted with from 1-3 substituentsindependently selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—,CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl.

In a second embodiment of the invention, compounds of formula (I) havesubformula (Ib):

where R¹¹ is C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or R^(e), eachof which is optionally substituted with from (i) 1-3 substituentsindependently selected from C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, R^(d) or R^(e); or (ii) 1, 2 or 3 R^(a)substituents; or (iii) 1, 2 or 3 R^(b) substituents; or (iv) 1, 2 or 3R^(c) substituents; or (v) 1, 2 or 3 R^(d) substituents; or (vi) 1, 2 or3 R^(f) groups; the subscript n is 1, 2, 3, 4 or 5 and the subscript mis 0, 1, 2 or 3. In some embodiments, R¹¹ is C₁₋₆alkyl, F, Cl, Br, I,—CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, ethyl, propyl, butyl, CH₃O, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In some embodiments, m is0. In other embodiments, the subscript n is 1, 2, 3 or 4. In someembodiments, n is 1, 2 or 3 and m is 1 or 2. All the other variables Y¹,Y² and Q are as defined in any of the embodiments described herein.

In a third embodiment of the invention, compounds of formula (I) havesubformula (Ic):

wherein R⁷ and R⁸ are each independently C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl or —X²R⁹, wherein the aliphatic or aromaticportion of R⁷ and R⁸ are each optionally substituted with from 1 to 3members independently selected from the group consisting ofC₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl and R^(e); and wherein X² is —NR¹⁰, O or S; R¹⁰ is H,C₁₋₆alkyl or aryl; and R⁹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl, wherein R⁹ is optionally substituted withfrom 1 to 3 R^(e) substituents. In some embodiments, R⁷ and R⁸ groupstaken together with the carbon atom to which they are attached form a 3to 8-membered carbocyclic ring or a 4 to 8-membered heterocyclic ringhaving from 1 to 2 heteroatoms as ring members selected from N, O or S,wherein the 3 to 8-membered carbocyclic ring or the 4 to 8-memberedheterocyclic ring is optionally substituted with from one to threegroups independently selected from C₁₋₆haloalkyl, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl or R^(e). All the other variables Y¹, Y²and Q are as defined in any of the embodiments described herein.

In a fourth embodiment of the invention, compounds of formula (I) havesubformula (Id):

wherein R¹² is H or R¹; or two adjacent R¹² together with the atoms towhich they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; wherein the 5 to6-membered-ring is optionally substituted with from 1-3 R^(d) or R^(e)substituents, and the subscript p is an integer of 1 to 5. In oneembodiment, p is 1. In another embodiment, p is 2. In yet anotherembodiment, p is 5 and two adjacent R¹² substituents together with theatoms to which they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; wherein the 5 to6-membered-ring is optionally substituted with from 1-3 R^(d) or R^(e)substituents, and each R¹² is independently H, R^(d) or R^(e). In someembodiments, the two adjacent R¹² together with the atoms to which theyare attached form an optionally substituted fused carbocyclic ring,including, but not limiting to, benzene, cyclopentane and cyclohexanerings. The substituents on the carbocyclic ring can be from 1-2 R^(d) orR^(e) groups. In other embodiments, two adjacent R¹² together with theatoms to which they are attached form an optionally substituted fusedheterocyclic ring, including, but not limiting to, pyrrole, furan,thiophen, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,piperazine, and hexahydropyrimidine rings. All the other variables Y², Qand Z are as defined in any of the embodiments described herein.

In a fifth embodiment of the invention, compounds of formula (I) havesubformula (Id-1):

wherein R¹² is H or R¹; or two adjacent R¹² together with the atoms towhich they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; wherein the 5 to6-membered-ring is optionally substituted with from 1-3 R^(d) or R^(e)substituents, and the subscript p is an integer of 1 to 5. In oneembodiment, p is 1. In another embodiment, p is 2. In yet anotherembodiment, p is 5 and two adjacent R¹² substituents together with theatoms to which they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; wherein the 5 to6-membered-ring is optionally substituted with from 1-3 R^(d) or R^(e)substituents, and the other three R¹² is each independently H, R^(d) orR^(e). In some embodiments, the two adjacent R¹² together with the atomsto which they are attached form an optionally substituted fusedcarbocyclic ring, including, but not limiting to, benzene, cyclopentane,cyclohexane and benzene rings. The substituents on the carbocyclic ringcan be from 1-2 R^(d) or R^(e) groups. In other embodiments, twoadjacent R¹² together with the atoms to which they are attached form anoptionally substituted fused heterocyclic ring, including, but notlimiting to, pyrrole, furan, thiophen, pyrazole, imidazole, oxazole,isoxazole, thiazole, isothiazole, pyridine, pyrazine, pyridazine,tetrahydrfuran, tetrahydropyran, tetrahydrothiophene, pyrazolidine,isoxazolidine, imidazolidine, oxazolidine, thiazolidine,isothiazolidine, piperidine, piperazine, and hexahydropyrimidine rings.All the other variables Y², Q, R⁴ and R⁵ are as defined in any of theembodiments described herein.

In a sixth embodiment of the invention, compounds of formula (I) havesubformula (Id-2):

All the variables R¹², p, m, n, Y², Q, and R¹¹ are as defined in any ofthe embodiments described herein. In some embodiments, R¹¹ is C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or R^(e), thesubscript m is an integer from 0 to 3, and the subscript n is an integerfrom 1 to 5.

In a seventh embodiment of the invention, compounds of formula (I) havesubformula (Id-3):

All the variables R¹², p, Y², Q, R⁷ and R⁸ are as defined in any of theembodiments described herein. In some embodiments, R⁷ and R⁸ are eachindependently C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or—X²R⁹, wherein the aliphatic or aromatic portion of R⁷ and R⁸ are eachoptionally substituted with from 1 to 3 members independently selectedfrom the group consisting of C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl and R^(e), provided at eachoccurrence, at least two of the R⁶, R⁷ and R⁸ groups are notsimultaneously hydrogen; and wherein X² is —NR¹⁰, O or S; R¹⁰ is H,C₁₋₆alkyl or aryl; and R⁹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl, wherein R⁹ is optionally substituted withfrom 1 to 3 R^(e) substituents.

In an eighth embodiment of the invention, compounds of formula (I) havesubformula (Ie):

wherein R³ is H or R¹; or two adjacent R³ together with the atoms towhich they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; and the subscript qis an integer of 1 to 4, where the 5 to 6-membered-ring is optionallysubstituted with from 1-3 R_(d) or R^(e)substituents. In one embodiment,q is 1. In another embodiment, q is 2. In yet another embodiment, q is 4and two adjacent R¹³ substituents together with the atoms to which theyare attached form a 5 to 6-membered ring having 0-2 heteroatoms as ringmembers selected from O, N or S; wherein the 5 to 6-membered-ring isoptionally substituted with from 1-3 R^(d) or R^(e) substituents, andthe other two R¹³ groups are each independently H, R^(d) or R^(e). Insome embodiments, the two adjacent R¹³ together with the atoms to whichthey are attached form an optionally substituted fused carbocyclic ring,including, but not limiting to, benzene, cyclopentane and cyclohexanerings. The substituents on the carbocyclic ring can be from 1-2 R^(d) orR^(e) groups. In other embodiments, two adjacent R¹³ groups togetherwith the atoms to which they are attached form an optionally substitutedfused heterocyclic ring, including, but not limiting to, pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,piperazine, and hexahydropyrimidine rings. All the other variables Y², Qand Z are as defined in any of the embodiments described herein.

In a ninth embodiment of the invention, compounds of formula (I) havesubformula (If):

R¹⁴ is H or R¹; or two adjacent R¹⁴ together with the atoms to whichthey are attached form a 5 to 6-membered ring having 0-2 heteroatoms asring members selected from O, N or S; and the subscript r is an integerof 1 to 3, where the 5 to 6-membered-ring is optionally substituted withfrom 1-3 R^(d) or R^(e)substituents. In one embodiment, r is 1. Inanother embodiment, r is 2. In yet another embodiment, r is 3 and twoadjacent R¹⁴ substituents together with the atoms to which they areattached form a 5 to 6-membered ring having 0-2 heteroatoms as ringmembers selected from O, N or S; wherein the 5 to 6-membered-ring isoptionally substituted with from 1-3 R^(d) or R^(e) substituents, andthe other R⁴ is H, R_(d) or R^(e). In some embodiments, the two adjacentR¹⁴ together with the atoms to which they are attached form anoptionally substituted fused carbocyclic ring, including, but notlimiting to, benzene, cyclopentane and cyclohexane rings. Thesubstituents on the carbocyclic ring can be from 1-2 R^(d) or R^(e)groups. In other embodiments, two adjacent R¹⁴ groups together with theatoms to which they are attached form an optionally substituted fusedheterocyclic ring, including, but not limiting to, pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,piperazine, and hexahydropyrimidine rings. All the other variables Y², Qand Z are as defined in any of the embodiments described herein.

In a tenth embodiment of the invention, compounds of formula (I) havesubformula (Ig):

R¹⁵ is H or R¹; or two adjacent R¹⁵ together with the atoms to whichthey are attached form a 5 to 6-membered ring having 0-2 heteroatoms asring members selected from O, N or S; and the subscript s is an integerof 1 to 3, where the 5 to 6-membered-ring is optionally substituted withfrom 1-3 R^(d) or R^(e)substituents. In one embodiment, s is 1. Inanother embodiment, s is 2. In yet another embodiment, s is 3 and twoadjacent R¹⁵ substituents together with the atoms to which they areattached form a 5 to 6-membered ring having 0-2 heteroatoms as ringmembers selected from O, N or S; wherein the 5 to 6-membered-ring isoptionally substituted with from 1-3 R^(d) or R^(e) substituents, andthe other R⁵ is H, R^(d) or R^(e). In some embodiments, the two adjacentR¹⁵ together with the atoms to which they are attached form anoptionally substituted fused carbocyclic ring, including, but notlimiting to, benzene, cyclopentane and cyclohexane rings. Thesubstituents on the carbocyclic ring can be from 1-2 R^(d) or R^(e)groups. In other embodiments, two adjacent R¹⁵ groups together with theatoms to which they are attached form an optionally substituted fusedheterocyclic ring, including, but not limiting to, pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,piperazine, and hexahydropyrimidine rings. In other embodiments, R¹⁵ ishalogen, —CN, —OH, —CF₃, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, —NO₂, benzyl,phenyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl,—OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b), —NHC(O)R^(b), —C(O)NHR^(b),—NHR^(b) or —NR^(b)R^(b). In some embodiments, R¹⁵ is F, Cl, Br, I, —CN,—OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido or methylcarbamoyl, isopropyl,1-pyrrolidinyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. All the other variables Y², Q and Z are asdefined in any of the embodiments described herein.

In an eleventh embodiment of the invention, compounds of formula (I)have subformula (Ig-1):

All the other variables R¹⁵, Y², Q and Z are as defined in any of theembodiments described herein. In a preferred embodiment, Y² is H. Insome embodiments, R¹⁵ is H or R¹. In some embodiments, R¹⁵ is R^(a),R^(b), R^(c), R^(d) or R^(e). In other embodiments, R¹⁵ is halogen, —CN,—OH, —CF₃, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, —NO₂, benzyl, phenyl,cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl,—OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b), —NHC(O)R^(b), —C(O)NHR^(b),—NHR^(b) or —NR^(b)R^(b). In some embodiments, R¹⁵ is F, Cl, Br, I, —CN,—OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido or methylcarbamoyl, isopropyl,1-pyrrolidinyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. In some embodiments, Z is —N(R⁴)(R⁵) or—N(CH₃)(R⁵). All the other variables are as defined in any of theembodiments described herein.

In a twelfth embodiment of the invention, compounds of formula (I) havesubformula (Ig-2):

All the variables R¹⁵, Y², Q, R¹¹, m and are as defined in any of theembodiments described herein. In a preferred embodiment, Y² is H. Insome embodiments, R¹⁵ is H or R¹. In some embodiments, R¹⁵ is R^(a),R^(b), R^(c), R^(d) or R^(e). In one embodiment, R¹⁵ is C₁₋₆alkyl. Inanother embodiment, R¹⁵ is C₃₋₆cycloalkyl. In yet another embodiment,R¹⁵ is heterocycloalkyl. The subscript m is an integer from 0 to 3. Thesubscript n is an integer from 1 to 5. In some embodiments, m is 0. Inother embodiments, the subscript n is 1, 2, 3 or 4. In some embodiments,n is 1, 2 or 3 and m is 1 or 2. In some embodiments, R¹¹ is C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl or R^(e). In some embodiments, R¹¹ is C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, heterocycloalkylalkyl or R^(e), each of which isoptionally substituted with from (i) 1-3 substituents independentlyselected from C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, R^(d) or R^(e); or (ii) 1, 2 or 3 R^(a) substituents;or (iii) 1, 2 or 3 R^(b) substituents; or (iv) 1, 2 or 3 R^(c)substituents; or (v) 1, 2 or 3 R^(d) substituents; or (vi) 1, 2 or 3R^(f) groups; the subscript n is 1, 2, 3, 4 or 5 and the subscript m is0, 1, 2 or 3. In other embodiments, R¹¹ is C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl orR^(e). In some embodiments, R¹¹ is halogen, C₁₋₆alkyoxycarbonyl,C₁₋₆alkyl, C₁₋₆alkyl-(CO)NH— or C₁₋₆alkyl-(CO)(C₁₋₆alkyl)N—. In certainembodiments, R¹¹ is methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—,vinyl, propen-3-yl or CH₃(CO)(CH₃)N—. In one embodiment of compounds offormula Ig-2, the subscript n is 1, m is 0 or 1. In another embodimentof compounds of formula Ig-2, the subscript n is 2, m is 0, 1 or 2. Inyet another embodiment, of compounds of formula Ig-2, the subscript n is3, m is 0, 1 or 2. All the other variables are as defined in any of theembodiments described herein.

In a thirteenth embodiment of the invention, compounds of formula (I)have subformula (Ig-3):

All the variables R¹⁵, Y², Q, R⁷ and R⁸ are as defined in any of theembodiments described herein. In a preferred embodiment, Y² is H. Insome embodiments, R¹⁵ is H or R¹. In some embodiments, R¹⁵ is R^(a),R^(b), R^(c), R^(d) or R^(e). In one embodiment, R¹⁵ is C₁₋₆alkyl. Inanother embodiment, R¹⁵ is C₃₋₆cycloalkyl. In yet another embodiment,R¹⁵ is heterocycloalkyl. In some embodiments, R⁷ and R⁸ are eachindependently C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₃₋₈cycloalkyl,C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or—X²R⁹, wherein the aliphatic or aromatic portion of R⁷ and R⁸ are eachoptionally substituted with from 1 to 3 members independently selectedfrom the group consisting of C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl and R^(e), provided at eachoccurrence, at least two of the R⁶, R⁷ and R⁸ groups are notsimultaneously hydrogen; and wherein X² is —NR¹⁰, O or S; R¹⁰ is H,C₁₋₆alkyl or aryl; and R⁹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, C₃₋₈cycloalkyl, C₃₋₈cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl, wherein R⁹ is optionally substituted withfrom 1 to 3 R^(e) substituents. In certain instances, —C(R⁷)(R⁸) is abranched C₃₋₆alkyl. In one embodiment, —C(R⁷)(R⁸) is isopropyl. Inanother embodiment, —C(R⁷)(R⁸) is sec-butyl. In yet another embodiment,—C(R⁷)(R⁸) is pentan-2-yl. In still another embodiment, —C(R⁷)(R⁸) ispentan-3-yl. All the other variables are as defined in any of theembodiments described herein.

In a fourteenth embodiment of the invention, compounds of formula (I)have subformula (Ih):

wherein Z¹ is O or S; R¹⁶ is H or R¹; or two adjacent R¹⁶ together withthe atoms to which they are attached form a 5 to 6-membered ring having0-2 heteroatoms as ring members selected from O, N or S; where the 5 to6-membered-ring is optionally substituted with from 1 to 3 R^(d) orR^(e) substituents; and the subscript t is an integer of 1 to 3. In oneembodiment, Z¹ is O. In another embodiment, Z¹ is S. In one embodiment,t is 1. In another embodiment, t is 2. In yet another embodiment, t is 3and two adjacent R¹⁶ substituents together with the atoms to which theyare attached form a 5 to 6-membered ring having 0-2 heteroatoms as ringmembers selected from O, N or S; wherein the 5 to 6-membered-ring isoptionally substituted with from 1-3 R^(d) or R^(e) substituents, andthe other R¹⁶ is H, R^(d) or R^(e). In some embodiments, the twoadjacent R¹⁶ together with the atoms to which they are attached form anoptionally substituted fused carbocyclic ring, including, but notlimiting to, benzene, cyclopentane and cyclohexane rings. Thesubstituents on the carbocyclic ring can be from 1-2 R^(d) or R^(e)groups. In other embodiments, two adjacent R¹⁶ groups together with theatoms to which they are attached form an optionally substituted fusedheterocyclic ring, including, but not limiting to, pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,piperazine, and hexahydropyrimidine rings. In other embodiments, R¹⁶ ishalogen, —CN, —OH, —CF₃, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, —NO₂, benzyl,phenyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl,—OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b), —NHC(O)R^(b), —C(O)NHR^(b),—NHR^(b) or —NRbRb. In some embodiments, R¹⁶ is F, Cl, Br, I, —CN, —OH,—CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl, 1-pyrrolidinyl,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino or 1-hydroxy-1-methylethyl. All the othervariables Y², Q and Z are as defined in any of the embodiments describedherein.

In a fifteenth embodiment of the invention, compounds of formula (I)have subformula (Ii):

wherein R¹⁸ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl orC₃₋₆cycloalkyl. R¹⁷ is H or R¹; or two adjacent R¹⁷ together with theatoms to which they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; or R¹⁷ and R¹⁸taken together with the atoms to which they are attached form a 5 to6-membered ring having 0-2 heteroatoms as ring members selected from O,N or S, where the 5 to 6-membered-ring is optionally substituted withfrom 1 to 3 R^(d) or R^(e)substituents; R¹⁸ is H, C₁₋₆alkyl orC₁₋₆haloalkyl; and the subscript u is an integer of 1 to 3. In oneembodiment, u is 1. In another embodiment, u is 2. In yet anotherembodiment, u is 3 and two adjacent R¹⁷ substituents together with theatoms to which they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; wherein the 5 to6-membered-ring is optionally substituted with from 1-3 R^(d) or R^(e)substituents, and the other R¹⁷ is H, R^(d) or R^(e). In otherembodiments, R¹⁷ and R¹⁸ taken together with the atoms to which they areattached form a 5 to 6-membered ring having 0-2 heteroatoms as ringmembers selected from O, N or S, where the 5 to 6-membered-ring isoptionally substituted with from 1 to 3 R^(d) or R^(e) substituents. Insome embodiments, (i) the two adjacent R¹⁷ together with the atoms towhich they are attached or (ii) R¹⁷ and R¹⁸ taken together with theatoms to which they are attached, form an optionally substituted fusedcarbocyclic ring, including, but not limiting to, benzene, cyclopentaneand cyclohexane rings. The substituents on the carbocyclic ring can befrom 1-2 R^(d) or R^(e)groups. In other embodiments, (i) two adjacentR¹⁷ groups together with the atoms to which they are attached or (ii)R¹⁷ and R¹⁸ taken together with the atoms to which they are attached,form an optionally substituted fused heterocyclic ring, including, butnot limiting to, pyrrole, furan, thiophene, pyrazole, imidazole,oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrazine,pyridazine, tetrahydrfuran, tetrahydropyran, tetrahydrothiophene,pyrazolidine, isoxazolidine, imidazolidine, oxazolidine, thiazolidine,isothiazolidine, piperidine, piperazine, and hexahydropyrimidine rings.In some embodiments, R¹⁷ is halogen, —CN, —OH, —CF₃, CF₃O—, C₁₋₆alkyl,C₁₋₆alkoxy, —NO₂, benzyl, phenyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl,cyclohexyl, cyclohexymethyl, —OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b),—NHC(O)R^(b), —C(O)NHR^(b), —NHR^(b) or —NR^(b)R^(b). In someembodiments, R¹⁷ is F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—,CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. In certain instances, R¹⁸ is H, C₁₋₆alkyl orC₁₋₆haloalkyl. In some embodiments, R¹⁸ is H, C₁₋₆alkyl or cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl,cyclopentylmethyl, cyclohexyl, or cyclohexylmethyl. In some embodiments,R¹⁸ is H or CH₃. All the other variables Y², Q and Z are as defined inany of the embodiments described herein.

In a sixteenth embodiment of the invention, compounds of formula (I)have subformula (Ij):

R¹⁹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkyl.R²⁰ is H or R¹; or two adjacent R²⁰ together with the atoms to whichthey are attached form a 5 to 6-membered ring having 0-2 heteroatoms asring members selected from O, N or S; or R²⁰ and R¹⁹ taken together withthe atoms to which they are attached form a 5 to 6-membered ring having0-2 heteroatoms as ring members selected from O, N or S; R¹⁹ is H,C₁₋₆alkyl or C₁₋₆haloalkyl; and the subscript v is an integer of 1 or 2,where the 5 to 6-membered-ring is optionally substituted with from 1 to3 R^(d) or R^(e) substituents. In one embodiment, v is 1. In someembodiments, two adjacent R²⁰ substituents together with the atoms towhich they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; wherein the 5 to6-membered-ring is optionally substituted with from 1-3 R^(d) or R^(e)substituents. In other embodiments, v is 2, R¹⁹ and R²⁰ taken togetherwith the atoms to which they are attached form a 5 to 6-membered ringhaving from 0-2 heteroatoms as ring members selected from O, N or S,where the 5 to 6-membered-ring is optionally substituted with from 1 to3 R^(d) or R^(e) substituents, and the other R²⁰ is H, R^(d) or R^(e).In some embodiments, (i) the two adjacent R²⁰ together with the atoms towhich they are attached or (ii) R¹⁹ and R²⁰ taken together with theatoms to which they are attached, form an optionally substituted fusedcarbocyclic ring, including, but not limiting to, cyclopentane,cyclohexane and benzene rings. The substituents on the carbocyclic ringcan be from 1-2 R^(d) or R^(e) groups. In other embodiments, (i) twoadjacent R¹⁹ groups together with the atoms to which they are attachedor (ii) R¹⁹ and R²⁰ taken together with the atoms to which they areattached, form an optionally substituted fused heterocyclic ring,including, but not limiting to, pyrrole, furan, thiophene, pyrazole,imidazole, oxazole, isoxazole, thiazole, isothiazole, pyridine,pyrazine, pyridazine, tetrahydrfuran, tetrahydropyran,tetrahydrothiophene, pyrazolidine, isoxazolidine, imidazolidine,oxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, andhexahydropyrimidine rings. In other embodiments, R²⁰ is halogen, —CN,—OH, —CF₃, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, —NO₂, benzyl, phenyl,cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl,—OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b), —NHC(O)R^(b), —C(O)NHR^(b),—NHR^(b) or —NR^(b)R^(b). In some embodiments, R²⁰ is F, Cl, Br, I, —CN,—OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl, 1-pyrrolidinyl,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino or 1-hydroxy-1-methylethyl. In certaininstances, R¹⁹ is H, C₁₋₆alkyl or C₁₋₆haloalkyl. In some embodiments,R¹⁹ is H, C₁₋₆alkyl or cyclopropyl, cyclopropylmethyl, cyclobutyl,cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, orcyclohexylmethyl. In some embodiments, R¹⁹ is H or CH₃. All the othervariables Y², Q and Z are as defined in any of the embodiments describedherein.

In a seventeenth embodiment of the invention, compounds of formula (I)have subformula (Ik):

Z² is O or S. The subscript w is 1 or 2. R²¹ is H or R¹; or two adjacentR²¹ together with the atoms to which they are attached form a 5 to6-membered ring having 0-2 heteroatoms as ring members selected from O,N or S, where the 5 to 6-membered-ring is optionally substituted withfrom 1 to 3 R^(d) or R^(e)substituents. In one embodiment, w is 1. Inanother embodiment, w is 2. In some embodiments, two adjacent R²¹substituents together with the atoms to which they are attached form a 5to 6-membered ring having 0-2 heteroatoms as ring members selected fromO, N or S; wherein the 5 to 6-membered-ring is optionally substitutedwith from 1-3 R^(d) or R^(e) substituents. In some embodiments, the twoadjacent R²¹ together with the atoms to which they are attached form anoptionally substituted fused carbocyclic ring, including, but notlimiting to, cyclopentane, cyclohexane and benzene rings. In certaininstances, the substituents on the carbocyclic ring can be from 1-2R^(d) or R^(e) groups. In other embodiments, two adjacent R²¹ groupstogether with the atoms to which they are attachedform an optionallysubstituted fused heterocyclic ring, including, but not limiting to,pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole,thiazole, isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,piperazine, and hexahydropyrimidine rings. In certain instances, thesubstituents on the heterocyclic ring can be from 1-2 R^(d) or R^(e)groups. In other embodiments, R²¹ is halogen, —CN, —OH, —CF₃, CF₃O—,C₁₋₆alkyl, C₁₋₆alkoxy, —NO₂, benzyl, phenyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl,cyclopentylmethyl, cyclohexyl, cyclohexymethyl, —OC(O)R^(b), —C(O)R^(b),—C(O)OR^(b), —NHC(O)R^(b), —C(O)NHR^(b), —NHR^(b) or —NR^(b)R^(b). Insome embodiments, R²¹ is F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—,CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. All the other variables Y², Q and Z are asdefined in any of the embodiments described herein.

In an eighteenth embodiment of the invention, compounds of formula (I)have subformula (Il):

Z³ is O, S or —N(R³⁰), where R³⁰ is H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₆cycloalkyl or C₃₋₆cycloalkyl. The subscript x is 1 or 2. R²² is H orR¹; or two adjacent R²² together with the atoms to which they areattached form a 5 to 6-membered ring having 0-2 heteroatoms as ringmembers selected from O, N or S, where the 5 to 6-membered-ring isoptionally substituted with from 1 to 3 R^(d) or R^(e) substituents. Inone embodiment, x is 1. In another embodiment, x is 2. In someembodiments, two adjacent R²² substituents together with the atoms towhich they are attached form a 5 to 6-membered ring having 0-2heteroatoms as ring members selected from O, N or S; wherein the 5 to6-membered-ring is optionally substituted with from 1-3 R^(d) or R^(e)substituents. In other embodiments, x is 2, R²² and R³⁰ taken togetherwith the atoms to which they are attached form a 5 to 6-membered ringhaving from 0-2 heteroatoms as ring members selected from O, N or S,where the 5 to 6-membered-ring is optionally substituted with from 1 to3 R^(d) or R^(e) substituents. In some embodiments, (i) the two adjacentR²² together with the atoms to which they are attached or (ii) R²² andR³⁰ taken together with the atoms to which they are attached, form anoptionally substituted fused carbocyclic ring, including, but notlimiting to, cyclopentane, cyclohexane and benzene rings. In certaininstances, the substituents on the carbocyclic ring can be from 1-2R^(d) or R^(e) groups. In other embodiments, (i) two adjacent R²² groupstogether with the atoms to which they are attached or (ii) R²² and R³⁰taken together with the atoms to which they are attached, form anoptionally substituted fused heterocyclic ring, including, but notlimiting to, pyrrole, furan, thiophene, pyrazole, imidazole, oxazole,isoxazole, thiazole, isothiazole, pyridine, pyrazine, pyridazine,tetrahydrfuran, tetrahydropyran, tetrahydrothiophene, pyrazolidine,isoxazolidine, imidazolidine, oxazolidine, thiazolidine,isothiazolidine, piperidine, piperazine, and hexahydropyrimidine rings.In other embodiments, R²² is halogen, —CN, —OH, —CF₃, CF₃O—, C₁₋₆alkyl,C₁₋₆alkoxy, —NO₂, benzyl, phenyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl,cyclohexyl, cyclohexymethyl, —OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b),—NHC(O)R^(b), —C(O)NHR^(b), —NHR^(b) or —NR^(b)R^(b). In someembodiments, R²² is F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—,CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. In certain instances, R³⁰ is H, C₁₋₆alkyl orC₁₋₆haloalkyl. In some embodiments, R³⁰ is H, C₁₋₆alkyl or cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl,cyclopentylmethyl, cyclohexyl, or cyclohexylmethyl. In some embodiments,R³⁰ is H or CH₃. All the other variables Y², Q and Z are as defined inany of the embodiments described herein.

In a nineteenth embodiment of the invention, compounds of formula (I)have subformula (Im):

R⁴⁰ is H or R¹; or two adjacent R⁴⁰ together with the atoms to whichthey are attached form a 5 to 6-membered ring having 0-2 heteroatoms asring members selected from O, N or S; and the subscript o is an integerof 1 to 3, where the 5 to 6-membered-ring is optionally substituted withfrom 1-3 R^(d) or R^(e)substituents. In one embodiment, the subscript ois 1. In another embodiment, the subscriot o is 2. In yet anotherembodiment, the subscript o is 3 and two adjacent R⁴⁰ substituentstogether with the atoms to which they are attached form a 5 to6-membered ring having 0-2 heteroatoms as ring members selected from O,N or S; wherein the 5 to 6-membered-ring is optionally substituted withfrom 1-3 R^(d) or R^(e)substituents, and the other R⁴⁰ is H, R^(d),R^(e) or R^(f). In some embodiments, the two adjacent R⁴⁰ together withthe atoms to which they are attached form an optionally substitutedfused carbocyclic ring, including, but not limiting to, benzene,cyclopentane and cyclohexane rings. The substituents on the carbocyclicring can be from 1-2 R^(d) or R^(e) groups. In other embodiments, twoadjacent R⁴⁰ groups together with the atoms to which they are attachedform an optionally substituted fused heterocyclic ring, including, butnot limiting to, pyrrole, furan, thiophene, pyrazole, imidazole,oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrazine,pyridazine, tetrahydrfuran, tetrahydropyran, tetrahydrothiophene,pyrazolidine, isoxazolidine, imidazolidine, oxazolidine, thiazolidine,isothiazolidine, piperidine, piperazine, and hexahydropyrimidine rings.In other embodiments, R⁴⁰ is halogen, —CN, —OH, —CF₃, CF₃O—, C₁₋₆alkyl,C₁₋₆alkoxy, —NO₂, benzyl, phenyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl,cyclohexyl, cyclohexymethyl, —OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b),—NHC(O)R^(b), —C(O)NHR^(b), —NHR^(b) or —NRbRb. In some embodiments, R⁴⁰is F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido ormethylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. All the other variables Y², Q and Z are asdefined in any of the embodiments described herein.

In a twentieth embodiment of the invention, compounds of formula (I)have subformula (In):

R⁴¹ is H or R¹; or two adjacent R⁴¹ together with the atoms to whichthey are attached form a 5 to 6-membered ring having 0-2 heteroatoms asring members selected from O, N or S; and the subscript n′ is an integerof 1 or 2, where the 5 to 6-membered-ring is optionally substituted withfrom 1-3 R^(d) or R^(e)substituents. In one embodiment, the subscript n′is 1. In another embodiment, the subscriot n′ is 2. In some embodiments,the two adjacent R⁴¹ substituents together with the atoms to which theyare attached form a 5 to 6-membered ring having 0-2 heteroatoms as ringmembers selected from O, N or S; wherein the 5 to 6-membered-ring isoptionally substituted with from 1-3 R^(d) or R^(e) substituents. Insome embodiments, the two adjacent R⁴¹ together with the atoms to whichthey are attached form an optionally substituted fused carbocyclic ring,including, but not limiting to, benzene, cyclopentane and cyclohexanerings. The substituents on the carbocyclic ring can be from 1-2 R^(d) orR^(e) groups. In other embodiments, two adjacent R⁴¹ groups togetherwith the atoms to which they are attached form an optionally substitutedfused heterocyclic ring, including, but not limiting to, pyrrole, furan,thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,piperazine, and hexahydropyrimidine rings. In other embodiments, R⁴¹ ishalogen, —CN, —OH, —CF₃, CF₃O—, C₁₋₆alkyl, C₁₋₆alkoxy, —NO₂, benzyl,phenyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl,—OC(O)R^(b), —C(O)R^(b), —C(O)OR^(b), —NHC(O)R^(b), —C(O)NHR^(b),—NHR^(b) or —NR^(b)R^(b). In some embodiments, R⁴¹ is F, Cl, Br, I, —CN,—OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido or methylcarbamoyl, isopropyl,1-pyrrolidinyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. All the other variables Y², Q and Z are asdefined in any of the embodiments described herein.

In some embodiments, the invention provides a compound selected from thegroup consisting of:

-   N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0012);-   5-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0013);-   5-(4-chlorophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0014);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0015);-   N-[2,4-difluoro-3-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide    (P-0016);-   N-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0017);-   5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0018);-   5-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0019);-   5-(4-chlorophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0020);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0021);-   N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0022);-   N-[3-[5-[2-(dimethylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0023);-   N-[2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide    (P-0024);-   N-[2,4-difluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide    (P-0025);-   3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0026);-   [2-fluoro-3-(methylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone    (P-0027);-   5-(4-cyanophenyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0028);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine    (P-0029);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine    (P-0030);-   5-[6-(dimethylamino)-3-pyridyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0031);-   5-(4-cyanophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0032);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine    (P-0033);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine    (P-0034);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine    (P-0035);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine;-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-phenyl-1H-pyrrolo[2,3-b]pyridine    (P-0036);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-phenyl-1H-pyrrolo[2,3-b]pyridine    (P-0037);-   5-bromo-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0038);-   5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0039);-   3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0040);-   3-benzyloxy-N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0041);-   1-cyclopropyl-N-[2-fluoro-3-[5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]methanesulfonamide    (P-0042);-   N-[2-fluoro-3-[5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0043);-   N-[3-[5-(2,4-dimethoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0044);-   N-[2-fluoro-3-[5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0045);-   N-[3-[5-[6-(dimethylamino)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0046);-   N-[2-fluoro-3-[5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0047);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0048);-   N-[3-[5-(4-cyano-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0049);-   N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0050);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0051);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0052);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine    (P-0053);-   5-(4-cyano-3-methoxy-phenyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0054);-   5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0055);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0056);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0057);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl)    sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0058);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine    (P-0059);-   5-(4-cyano-3-methoxy-phenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0060);-   5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0061);-   N-[2-fluoro-3-[5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0062);-   N-[2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide    (P-0063);-   5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0064);-   N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methoxy-ethane    sulfonamide (P-0065);-   methyl    3-[[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl]propanoate    (P-0066);-   N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide    (P-0067);-   [3-(ethylsulfamoylamino)-2-fluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone    (P-0068);-   [3-(ethylsulfamoylamino)-2-fluoro-phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone    (P-0069);-   3-[2-fluoro-3-[[isobutyl(methyl)sulfamoyl]amino]benzoyl]-5-iodo-1H-pyrrolo[2,3-b]pyridine    (P-0070);-   [2-fluoro-3-(isopropylsulfamoylamino)phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone    (P-0071);-   3-[2-fluoro-3-[[isobutyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0072);-   3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0073);-   N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methyl-pyrrolidine-1-sulfonamide    (P-0074);-   3-[2-fluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0075);-   5-[6-(dimethylamino)-3-pyridyl]-3-[3-[[ethyl(methyl-3-3ethylmethyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0076);-   5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0077);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0078);-   5-[4-(1-cyanocyclopropyl)phenyl]-3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0079);-   5-[4-(1-cyanocyclopropyl)phenyl]-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0080);-   5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0081);-   5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0082);-   3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0083);-   3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0084);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0085);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0086);-   5-(6-cyclopropyl-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0087);-   3,3-difluoro-N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]azetidine-1-sulfonamide    (P-0088);-   4-[[(1    S)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine    (P-0089);-   N-[3-[5-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0090);-   N-[3-[5-(2-cyanopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0091);-   N-[2-fluoro-3-[5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0092);-   N-[3-[5-(5-cyano-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0093);-   N-[2-fluoro-3-[5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0095);-   5-(2-cyanopyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0096);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0097);-   5-(5-cyano-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0098);-   5-(6-cyano-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0099);-   5-(2-cyanopyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0100);-   5-(5-cyano-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0101);-   5-(6-cyano-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0102);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine    (P-0103);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine    (P-0104);-   N-[2-fluoro-3-[5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0105);-   5-[2-(dimethylamino)pyrimidin-5-yl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0106);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0107);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0108);-   N-[2-fluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0109);-   3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-iodo-1H-pyrrolo[2,3-b]pyridine    (P-0110);-   3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0111);-   3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0112);-   5-(6-cyclopropyl-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0113);-   5-(6-cyclopropyl-3-pyridyl)-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0114);-   3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(6-cyclopropyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine    (P-0115);-   3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0116);-   [2-fluoro-3-(propylsulfamoylamino)phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone    (P-0117);-   [2-fluoro-3-(propylsulfamoylamino)phenyl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone    (P-0223);-   N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide    (P-0024);-   N-[2-fluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide    (P-0225);-   N-[3-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide    (P-0226);-   N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide    (P-00227);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide    (P-0228);-   N-[2-fluoro-3-[5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide    (P-0229);-   N-[3-[5-[6-(dimethylamino)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide    (P-0230);-   N-[2-fluoro-3-[5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide    (P-0231);-   N-[3-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0232);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0233);-   N-[2-fluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide;    (P-0235);-   N-[2-fluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide    (P-0236);-   5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0237);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0238);-   5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0239);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0240);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0241);-   [2-fluoro-3-(propylsulfamoylamino)phenyl]-[5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone    (P-0242);-   1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylic    acid (P-0243);-   3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(5-ethoxypyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0244);-   5-[4-(1-cyano-1-methyl-ethyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-H-pyrrolo[2,3-b]pyridine    (P-0245);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3,3-dimethyl-pyrrolidine-1-sulfonamide    (P-0246);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide    (P-0247);-   N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0248);-   3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0249);-   [5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[2-fluoro-3-(propylsulfamoylamino)phenyl]methanone    (P-0251);-   3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0252);-   1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxamide    (P-0253);-   methyl    1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylate    (P-0254);-   5-[4-(1-cyano-1-methyl-ethyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-H-pyrrolo[2,3-b]pyridine    (P-0255);-   5-(2-ethoxypyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0256);-   ethyl    1-[[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl]pyrrolidine-2-carboxylate    (P-0257);-   4-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]morpholine    (P-0258);-   4-[3-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]morpholine    (P-0259);-   N-[2,4-difluoro-3-[5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0260);-   N-[2,4-difluoro-3-[5-(2-piperazin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0261);-   N-[2,4-difluoro-3-[5-[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0262);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine    (P-0263);-   tert-butyl    4-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]piperazine-1-carboxylate    (P-0264);-   N-[2,4-difluoro-3-[5-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0265);-   N-[2,4-difluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0266);-   N-[1-[[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]sulfamoyl]pyrrolidin-3-yl]-N-methyl-acetamide    (P-0267);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-piperazin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0268);-   N-[3-[5-[2-(azetidin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0269);-   N-[2,4-difluoro-3-[5-(2-methoxythiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0270);-   (3R)—N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide    (P-0271);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-(methylamino)pyrrolidine-1-sulfonamide    (P-0272);-   N-[2,4-difluoro-3-[5-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0273);-   N-[3-(5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0274);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]amino-2,6-difluoro-benzoyl-5-[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine    (P-0275);-   5-[3-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0276);-   5-[2-(azetidin-1-yl)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0277);-   N-[3-[5-(2-aminopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0279);-   N-[3-[5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0280);-   N-[2-fluoro-3-[5-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0281);-   N-[2,4-difluoro-3-[5-(2-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0282);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-fluoro-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine    (P-0283);-   N-[2,4-difluoro-3-[5-(2-morpholino-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0284);-   N-[2,4-difluoro-3-[5-[2-(4-methylpiperazin-1-yl)-4-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0285);-   N-[3-[5-[2-(cyclobutoxy)-4-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0286);-   N-[2,4-difluoro-3-[5-(2-methoxy-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0287);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3,3-difluoro-pyrrolidine-1-sulfonamide    (P-0288);-   (3S)—N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide    (P-0289);-   methyl    2-[[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]sulfamoyl]propanoate    (P-0291);-   5-[2-(dimethylamino)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0292);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0293);-   N-[2,4-difluoro-3-[5-[6-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0294);-   N-[3-[5-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0295);-   5-cyclobutyl-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0297);-   5-cyclopropyl-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0298);-   N-[3-[5-(6-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0299);-   5-(4-cyanophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0300);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine    (P-0301);-   5-[3-(dimethylamino)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0302);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(4-pyrrolidin-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridine    (P-0303);-   2-[4-[3-[3-[[ethyl(methyl)    sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-5-methyl-1,3,4-oxadiazole    (P-0304);-   2-[4-[3-[3-[[ethyl(methyl)    sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-5-(methylamino)-1,3,4-thiadiazole    (P-0305);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[5-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine    (P-0306);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine    (P-0307);-   5-[4-(diethylamino)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0308);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-oxoindolin-6-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0309);-   3-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-thienyl]-5-methyl-1,2,4-oxadiazole    (P-0310);-   2-amino-6-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinazoline    (P-0311);-   N-cyclopropyl-5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide    (P-0312);-   2-(dimethylamino)-6-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinazoline    (P-0313);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(1-hydroxycyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine    (P-0314);-   5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]thiazole    (P-0315);-   4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(1-hydroxy-1-methyl-ethyl)thiazole    (P-0316);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-methoxypyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0317);-   N-[2,4-difluoro-3-[5-(6-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0318);-   N-[2,4-difluoro-3-[5-[6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0319);-   (3S)—N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide    (P-0320);-   N-[2-fluoro-3-[5-(6-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0321);-   N-[2-fluoro-3-[5-[6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0322);-   N-[2-fluoro-3-[5-[6-(4-methylpiperazin-1-yl)-2-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0324);-   N-[2-fluoro-3-[5-(4-methoxypyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0325);-   N-[2-fluoro-3-[5-(4-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0326);-   (3R)—N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide    (P-0327);-   [5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[2,6-difluoro-3-(methylsulfamoylamino)phenyl]methanone    (P-0334);-   [5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[3-(ethylsulfamoylamino)-2,6-difluoro-phenyl]methanone    (P-0335);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-(sulfamoylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0336);-   N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide    (P-0337);-   (3R)—N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide    (P-0338);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide    (P-0339);-   5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0340);-   N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide    (P-0342);-   5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methoxy-thiazole    (P-0343);-   3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridine    (P-0344);-   N-[2,4-difluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide    (P-0345);-   N-[3-(5-cyclobutyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide    (P-0346);-   N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide    (P-0347);-   1-allyl-N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]cyclopropanesulfonamide    (P-0348);-   N-[2,4-difluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide    (P-0349);-   N-[2,4-difluoro-3-[5-(5-methoxy-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide    (P-0350); and-   N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]cyclopropanesulfonamide    (P-0351);    or pharmaceutically acceptable salts, hydrates, solvates, tautomers    or isomers thereof. In some embodiments, the invention provides the    above selected compounds and pharmaceutically acceptable salts    thereof. In other embodiments, the invention provides the above    selected compounds and pharmaceutically acceptable salts and    tautomers and isomers thereof.

In other embodiments, the invention provides a compound selected fromany of P-0108 to P-0222 as set forth in Table 3 and pharmaceuticallyacceptable salts, hydrates, solvates, tautomers and isomers thereof. Insome embodiments, the invention provides any of the above selectedcompounds and pharmaceutically acceptable salts thereof. In someembodiments, the invention provides any of the above selected compoundsand pharmaceutically acceptable salts and tautomers and isomers thereof.

In some embodiments, when Y¹ is optionally substituted 2-pyridyl,3-pyridyl or 4-pyridyl, Z is other than —N(CH₃)(CH₃) or —N(R⁴)₂, whereinR⁴ is C₁₋₆alkyl. In some embodiments, when Y¹ is phenyl, Z is other than—N(CH₃)(CH₃) or —N(R⁴)₂, wherein R⁴ is C₁₋₆alkyl. In other embodiments,when Y¹ is halogen, Z is other than —N(CH₃)(CH₃), —N(Et)₂, 1-pyrrolinyl,1-piperidinyl, 4-morpholinyl or —N(R⁴)₂, wherein R⁴ is C₁₋₆alkyl. Insome embodiments, when Y¹ is CH₃ or C₁₋₆alkyl, Z is other than—N(CH₃)(CH₃), —N(Et)₂, 1-pyrrolinyl, 1-piperridinyl, 4-morpholinyl or—N(R⁴)₂, wherein R⁴ is C₁₋₆alkyl. In some embodiments, when Y¹ is CH₃O—or C₁₋₆alkoxy, Z is other than —N(CH₃)(CH₃), —N(Et)₂, 1-pyrrolinyl,1-piperridinyl, 4-morpholinyl or —N(R⁴)₂, wherein R⁴ is C₁₋₆alkyl. Insome embodiments, when Y¹ is CN, Z is other than —N(CH₃)(CH₃), —N(Et)₂,1-pyrrolinyl, 1-piperridinyl, 4-morpholinyl or —N(R⁴)₂, wherein R⁴ isC₁₋₆alkyl. In certain instances, when Y¹ is halogen, —CH₃, —CN, —OMe or2-methoxypyrimidin-5-yl, Z is other than C₃₋₆cycloalkyl. In otherinstances, when Y¹ is 1-methyl-4-pyrazolyl, 3-methylsulfonylphenyl or3-methylsulfonylaminophenyl, Z is other than C₃₋₆cycloalkyl. In otherinstances, when Y¹ is C₁₋₆alkyl or C₁₋₆alkoxy, Z is other thanC₃₋₆cycloalkyl. In other instances, when Y¹ is 1-C₁₋₆alkyl-4-pyrazolyl,Z is other than cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Inother instances, when Y¹ is 1-C₁₋₆alkyl-4-pyrazolyl, Z is other thanC₃₋₆cycloalkyl. In other instances, when Y¹ is methylsulfonylphenyl ormethylsulfonylaminophenyl, Z is other than cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In other instances, when Y¹ ismethylsulfonylphenyl or methylsulfonylaminophenyl, Z is other thanC₃₋₆cycloalkyl. In some instances, when Y¹ is 3-C₁₋₆alkylsulfonylphenylor 3-C₁₋₆alkylsulfonylaminophenyl, Z is other than cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl. In other instances, when Y¹ is3-C₁₋₆alkylsulfonylphenyl or 3-C₁₋₆alkylsulfonylaminophenyl, Z is otherthan C₃₋₆cycloalkyl.

The following compounds in Table 1 are excluded from the genericformulas I and Ia to In:

TABLE 13-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine;5-bromo-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-phenyl-1H-pyrrolo[2,3-b]pyridine;N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]piperidine-1-sulfonamide;5-(4-chlorophenyl)-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;5-chloro-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[3-[dimethylsulfamoyl(methyl)amino]-2,6-difluoro-phenyl]methanone;N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide;N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide;N-[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide;N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide;5-cyano-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine;5-chloro-3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;5-cyano-3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine;3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine;N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]morpholine-4-sulfonamide;N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]morpholine-4-sulfonamide;N-[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]morpholine-4-sulfonamide;N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]morpholine-4-sulfonamide;3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine;N-[2,4-difluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide;3-[3-(diethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine;N-[2,4-difluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]morpholine-4-sulfonamide;5-cyano-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide;N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]morpholine-4-sulfonamide;N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide;5-(4-chlorophenyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine;3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine; Propane-2-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Pyrrolidine-1-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Propane-2-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Propane-2-sulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Propane-2-sulfonic acid{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Butane-2-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Pentane-2-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Butane-2-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Pentane-2-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Butane-2-sulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Pentane-2-sulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Pentane-2-sulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Butane-2-sulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Butane-2-sulfonic acid{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclobutanesulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Cyclobutanesulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Cyclohexanesulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Cyclopentanesulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Cyclohexanesulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Cyclopentanesulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Cyclopentanesulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Cyclohexanesulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Cyclobutanesulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Cyclopentanesulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Cyclohexanesulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Cyclohexanesulfonic acid{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclopentanesulfonic acid{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclobutanesulfonic acid{2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Pyrrolidine-1-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Pyrrolidine-1-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Pyrrolidine-1-sulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Pyrrolidine-1-sulfonic acid[2,4-difluoro-3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; N,N-dimethylamino-sulfonic acid[2,4-difluoro-3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; N,N-dimethylamino-sulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; N,N-diethylamino-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; N,N-diethylamino-sulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; N,N-diethylamino-sulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; N,N-diethylamino-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Morpholine-4-sulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Morpholine-4-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Morpholine-4-sulfonic acid[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Morpholine-4-sulfonic acid[2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Propane-2-sulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide;Butane-2-sulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide;Cyclohexanesulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide; Cyclopentanesulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide; Cyclobutanesulfonic acid[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide; Cyclopropanesulfonic acid{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclohexanesulfonic acid{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclopropanesulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide; Cyclohexanesulfonic acid[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Cyclohexanesulfonic acid{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclopentanesulfonic acid{4-fluoro-3-[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclohexanesulfonic acid{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclopentanesulfonic acid{4-fluoro-3-[5-(3-methanesulfonylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide; Cyclopentanesulfonic acid[4-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; Piperidine-1-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-amide; N,N-dimethylamino-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide; Pyrrolidine-1-sulfonic acid[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide.

In another aspect, the present invention provides a method for preparinga compound of formulas (I) to (In). The method includes contacting acompound having formula II:

with an agent selected from Y¹-G¹ (III) or A¹-S(O)₂—Z(IV) underconditions sufficient to form a compound having formulas (V) or (VI):

reacting (i) a compound of formula (V) with a compound of formula (IV),or (ii) a compound of formula (VI) with a compound of formula (III)under conditions sufficient to form the compound of formula (I); andwherein E¹ is halogen, tosylate or mesylate; G¹ is —B(OR²⁵)₂ or—Sn(Bu)₃, wherein R²⁵ is —OH, alkyl or two —OR²⁵ substituents togetherwith the boron atom to which they are attached to form an optionallysubstituted 5 or 6-membered ring; A¹ is a leaving group, which can bereadily displaced by an arylamino group; and P¹ is H or an aminoprotecting group. In some instances, the substituents for the 5 or6-membered ring are 1 to 4 members R^(e) groups. In some embodiments,the reaction of compounds of formula (II) with In one embodiment, E¹ isCl, Br or I. In another rembodiment, E¹ is tosylate, mesylate ortriflate. In one embodiment, G¹ is —B(OH)₂. In another embodiment, G¹ is2-hydroxy-1,3,2-benzodioxaborole or2-hydroxy-4,4,5,5-tetramethyl-1,3,2-benzodioxaboro. In anotherembodiment, G¹ is —Sn(Bu)₃. In one embodiment, A¹ is Cl or Br. Inanother embodiment, A¹ is tosylate or mesylate. In one embodiment, P¹ isH. The substituents Y¹, Y², Q and Z are as defined in any of formulas(I) to (In) and any of the embodiments disclosed herein.

In some embodiments, the method includes contacting a compound offormula (II) with an agent of formula (III): Y¹-G¹ to form a compound offormula (V), followed by reacting a compound of formula (V) with anagent of formula (IV): A¹-S(O)₂—Z to form a compound of formula (I). Inother embodiments, the method includes contacting a compound of formula(II) with an agent of formula (IV): A¹-S(O)₂—Z to form a compound offormula (VI), followed by reacting a compound of formula (VI) with anagent of formula (III): Y¹-G¹ to form a compound of formula (I).

In yet other embodiments, the invention provides a method for preparinga compound of formulas (I) to (In). The method includes reacting acompound having formula II:

with a compound of formula (IV): A¹-S(O)₂—Z under conditions sufficientto form a compound having formula (VI):

contacting a compound of formula (VI) with a compound of the formula:Y¹-E² and a compound of the formula: (OR³¹)₂B—B(OR³¹)₂ in the presenceof a palladium complex under conditions sufficient to form the compoundof formula (I), wherein R³¹ is —OH, alkyl or two —OR³¹ substituentstogether with the boron atom to which they are attached to form a 5 or6-membered ring; and wherein E¹ and E² are each independently halogen,tosylate or mesylate; A¹ is a leaving group; and P¹ is H or an aminoprotecting group. Both Pd(O) and Pd(II) complexes can be used. In someembodiments, E¹ is Cl, Br, I, tosylate or mesylate. In some embodiments,E² is Cl, Br, I, tosylate or mesylate. In certain instances, thepalladium complexes include, but are not limited to, Pd(PPh₃)₄,bis(diphenylphosphino)ferrocene]dichloropalladium and the like. Thesubstituents Y¹, Y², Q and Z are as defined in any of formulas (I) to(In) and any of the embodiments disclosed herein.

In another aspect, the invention provides a compound having formula(VIII):

wherein R³² and R³³ are each independently H, optionally substitutedalkyl, optionally substituted arylalkyl or optionally substituted aryl.In ome embodiments, the aryl or alkyl portion of R³² or R³³ isoptionally substituted with from 1 to 4 R^(e) substituents; or R³² andR³³ together with the oxygen atoms to which they are attached form a 5-or 6-membered ring, wherein the 5- or 6-membered ring is optionallysubstituted with from 1 to 4 R^(e) groups or fused with an optionallysubstituted 5- or 6-membered aromatic ring. The substituents Y², Q and Zin formula VIII are as defined in in any of formulas (I) to (In) and anyof the embodiments as described herein.

In some embodiments, the compounds of formula VIII have sub formulaVIIIa:

R³⁴, R³⁵, R³⁶ and R³⁷ are each independently R^(e) or R^(f). In certaininstances, R³⁴, R³⁵, R³⁶ and R³⁷ are each independently C₁₋₆ alkyl. Inother instances, R³⁴, R³⁵, R³⁶ and R³⁷ are CH₃. The substituents Y², Qand Z in formula VIIIa are as defined in any of formulas (I) to (In) andany of the embodiments as described herein.

In some embodiments, the compounds of formula VIII have sub formulaVIIIb:

The subscript y is an integer of 1 to 4. Each R³⁸ is independently H,R^(e) or R^(f). The substituents Y², Q and Z in formula VIIIb are asdefined in any of formulas (I) to (In) and any of the embodiments asdescribed herein.

In some embodiments, the compounds of formula VIII have subformulaVIIIc:

The subscript z is an integer of 1 to 4. Each R³⁹ is independently H,R^(e) or R^(f). The substituents Y², Q and Z in formula VIIIc are asdefined in any of formulas (I) to (In) and any of the embodiments asdescribed herein.

Organic Synthetic Techniques

A wide array of organic synthetic techniques exist in the art tofacilitate the construction of potential modulators. Many of theseorganic synthetic methods are described in detail in standard referencesources utilized by those skilled in the art. One example of such areference is March, 1994, Advanced Organic Chemistry; Reactions,Mechanisms and Structure, New York, McGraw Hill. Thus, the techniquesuseful to synthesize a potential modulator of kinase function arereadily available to those skilled in the art of organic chemicalsynthesis.

Alternative Compound Forms or Derivatives

Compounds contemplated herein are described with reference to bothgeneric formulae and specific compounds. In addition, inventioncompounds may exist in a number of different forms or derivatives, allwithin the scope of the present invention. Alternative forms orderivatives, include, for example, (a) prodrugs, and active metabolites(b) tautomers, isomers (including stereoisomers and regioisomers), andracemic mixtures (c) pharmaceutically acceptable salts and (d) solidforms, including different crystal forms, polymorphic or amorphoussolids, including hydrates and solvates thereof, and other forms.

(a) Prodrugs and Metabolites

In addition to the present formulae and compounds described herein, theinvention also includes prodrugs (generally pharmaceutically acceptableprodrugs), active metabolic derivatives (active metabolites), and theirpharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. For example, some prodrugs are esters of the activecompound; during metabolysis, the ester group is cleaved to yield theactive drug. Esters include, for example, esters of a carboxylic acidgroup, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenolgroups. In this context, a common example is an alkyl ester of acarboxylic acid. Prodrugs may also include variants wherein an —NH groupof the compound has undergone acylation, such as the 1-position of the1H-pyrrolo[2,3-b]pyridine ring, or the nitrogen of the sulfonamide groupof compounds as described herein, where cleavage of the acyl groupprovides the free —NH group of the active drug. Some prodrugs areactivated enzymatically to yield the active compound, or a compound mayundergo further chemical reaction to yield the active compound. Prodrugsmay proceed from prodrug form to active form in a single step or mayhave one or more intermediate forms which may themselves have activityor may be inactive.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollowing types:

Oxidative reactions: Oxidative reactions are exemplified withoutlimitation by reactions such as oxidation of alcohol, carbonyl, and acidfunctionalities, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative 0- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive reactions: Reductive reactions are exemplified withoutlimitation by reactions such as reduction of carbonyl functionalitites,reduction of alcohol functionalities and carbon-carbon double bonds,reduction of nitrogen-containing functional groups, and other reductionreactions.

Reactions without change in the oxidation state: Reactions withoutchange in the state of oxidation are exemplified without limitation byreactions such as hydrolysis of esters and ethers, hydrolytic cleavageof carbon-nitrogen single bonds, hydrolytic cleavage of non-aromaticheterocycles, hydration and dehydration at multiple bonds, new atomiclinkages resulting from dehydration reactions, hydrolyticdehalogenation, removal of hydrogen halide molecule, and other suchreactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, application. Ser. No.10/656,838, incorporated herein by reference.) Such carrier prodrugs areoften advantageous for orally administered drugs. In some instances, thetransport moiety provides targeted delivery of the drug, for example thedrug may be conjugated to an antibody or antibody fragment. Carrierprodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxyl groups with lipophilic carboxylic acids,or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, supra.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic processes in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.For example, in some compounds, one or more alkoxy groups can bemetabolized to hydroxyl groups while retaining pharmacologic activityand/or carboxyl groups can be esterified, e.g., glucuronidation. In somecases, there can be more than one metabolite, where an intermediatemetabolite(s) is further metabolized to provide an active metabolite.For example, in some cases a derivative compound resulting frommetabolic glucuronidation may be inactive or of low activity, and can befurther metabolized to provide an active metabolite.

Metabolites of a compound may be identified using routine techniquesknown in the art, and their activities determined using tests such asthose described herein. See, e.g., Bertolini et al., 1997, J. Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757;Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

(b) Tautomers, Stereoisomers, and Regioisomers

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood that theformulae provided herein are intended to represent any tautomeric formof the depicted compounds and are not to be limited merely to thespecific tautomeric form depicted by the drawings of the formulae.

Likewise, some of the compounds according to the present invention mayexist as stereoisomers, i.e. having the same atomic connectivity ofcovalently bonded atoms yet differing in the spatial orientation of theatoms. For example, compounds may be optical stereoisomers, whichcontain one or more chiral centers, and therefore, may exist in two ormore stereoisomeric forms (e.g. enantiomers or diastereomers). Thus,such compounds may be present as single stereoisomers (i.e., essentiallyfree of other stereoisomers), racemates, and/or mixtures of enantiomersand/or diastereomers. As another example, stereoisomers includegeometric isomers, such as cis- or trans-orientation of substituents onadjacent carbons of a double bond. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe present invention. Unless specified to the contrary, all suchsteroisomeric forms are included within the formulae provided herein.

In some embodiments, a chiral compound of the present invention is in aform that contains at least 80% of a single isomer (60% enantiomericexcess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70%e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5%(95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understoodby those skilled in the art, an optically pure compound having onechiral center is one that consists essentially of one of the twopossible enantiomers (i.e., is enantiomerically pure), and an opticallypure compound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. In some embodiments,the compound is present in optically pure form, such optically pure formbeing prepared and/or isolated by methods known in the art (e.g. byrecrystallization techniques, chiral synthetic techniques (includingsynthesis from optically pure starting materials), and chromatographicseparation using a chiral column.

(c) Pharmaceutically Acceptable Salts

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound. Thus,compounds described herein and recited in any of the claims can be inthe form of pharmaceutically acceptable salts, or can be formulated aspharmaceutically acceptable salts. Contemplated pharmaceuticallyacceptable salt forms include, without limitation, mono, bis, tris,tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic inthe amounts and concentrations at which they are administered. Thepreparation of such salts can facilitate the pharmacological use byaltering the physical characteristics of a compound without preventingit from exerting its physiological effect. Useful alterations inphysical properties include lowering the melting point to facilitatetransmucosal administration and increasing the solubility to facilitateadministering higher concentrations of the drug. A compound of theinvention may possess a sufficiently acidic, a sufficiently basic, orboth functional groups, and accordingly can react with any of a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt.

Pharmaceutically acceptable salts include acid addition salts such asthose containing chloride, bromide, iodide, hydrochloride, acetate,phenylacetate, acrylate, ascorbate, aspartate, benzoate,2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate,hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate,citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate,glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate,isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate,lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate,mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate,orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate,3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate,pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate,suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e. besylate),ethanesulfonate (i.e. esylate), ethane-1,2-disulfonate,2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonate (i.e.mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e.napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate),xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate.These pharmaceutically acceptable acid addition salts can be preparedusing the appropriate corresponding acid.

When acidic functional groups, such as carboxylic acid or phenol arepresent, pharmaceutically acceptable salts also include basic additionsalts such as those containing benzathine, chloroprocaine, choline,ethanolamine, diethanolamine, triethanolamine, t-butylamine,dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine,meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine,procaine, aluminum, calcium, copper, iron, lithium, magnesium,manganese, potassium, sodium, zinc, ammonium, and mono-, di-, ortri-alkylamines (e.g. diethylamine), or salts derived from amino acidssuch as L-histidine, L-glycine, L-lysine, and L-arginine. For example,see Remington's Pharmaceutical Sciences, 19^(th) ed., Mack PublishingCo., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceuticallyacceptable base addition salts can be prepared using the appropriatecorresponding base.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent. If the particularcompound is an acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an appropriate inorganic or organic base.

(d) Other Compound Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, or may be formulated as co-crystals, or may be inan amorphous form, or may be any combination thereof (e.g. partiallycrystalline, partially amorphous, or mixtures of polymorphs) all ofwhich are intended to be within the scope of the present invention andspecified formulae. Whereas salts are formed by acid/base addition, i.e.a free base or free acid of the compound of interest forms an acid/basereaction with a corresponding addition base or addition acid,respectively, resulting in an ionic charge interaction, co-crystals area new chemical species that is formed between neutral compounds,resulting in the compound and an additional molecular species in thesame crystal structure.

In some instances, compounds of the invention are complexed with an acidor a base, including base addition salts such as ammonium, diethylamine,ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine,meglumine; acid addition salts, such as acetate, acetylsalicylate,besylate, camsylate, citrate, formate, fumarate, glutarate,hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate,succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acidssuch as alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine or valine. In combining the compound of theinvention with the acid or base, an amorphous complex is preferablyformed rather than a crystalline material such as a typical salt orco-crystal. In some instances, the amorphous form of the complex isfacilitated by additional processing, such as by spray-drying,mechanochemical methods such as roller compaction, or microwaveirradiation of the parent compound mixed with the acid or base. Suchmethods may also include addition of ionic and/or non-ionic polymersystems, including, but not limited to, hydroxypropyl methyl celluloseacetate succinate (HPMCAS) and methacrylic acid copolymer (e.g.Eudragit® L100-55), that further stabilize the amorphous nature of thecomplex. Such amorphous complexes provide several advantages. Forexample, lowering of the melting temperature relative to the free basefacilitiates additional processing, such as hot melt extrusion, tofurther improve the biopharmaceutical properties of the compound. Also,the amorphous complex is readily friable, which provides improvedcompression for loading of the solid into capsule or tablet form.

Additionally, the formulae are intended to cover hydrated or solvated aswell as unhydrated or unsolvated forms of the identified structures. Forexample, the indicated compounds include both hydrated and non-hydratedforms. Other examples of solvates include the structures in combinationwith a suitable solvent, such as isopropanol, ethanol, methanol,dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine.

IV. Formulations and Administration

In another aspect, the present invention provides pharmaceuticalcompositions comprising/including a pharmaceutically acceptable carrieror excipient and a compound of the invention described herein or apharmaceutically acceptable salt or solvate thereof. In an exemplaryembodiment, the present invention provides a pharmaceutical formulationcomprising/including a compound as described herein. In one embodiment,the compound has any of formulas I, and Ia to In.

The methods and compounds will typically be used in therapy for humansubjects. However, they may also be used to treat similar or identicalindications in other animal subjects. Compounds described herein can beadministered by different routes, including injection (i.e. parenteral,including intravenous, intraperitoneal, subcutaneous, andintramuscular), oral, transdermal, transmucosal, rectal, or inhalant.Such dosage forms should allow the compound to reach target cells. Otherfactors are well known in the art, and include considerations such astoxicity and dosage forms that retard the compound or composition fromexerting its effects. Techniques and formulations generally may be foundin Remington: The Science and Practice of Pharmacy, 21^(st) edition,Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (herebyincorporated by reference herein).

In some embodiments, compositions will comprise pharmaceuticallyacceptable carriers or excipients, such as fillers, binders,disintegrants, glidants, lubricants, complexing agents, solubilizers,and surfactants, which may be chosen to facilitate administration of thecompound by a particular route. Examples of carriers include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, types of starch, cellulose derivatives, gelatin, lipids,liposomes, nanoparticles, and the like. Carriers also includephysiologically compatible liquids as solvents or for suspensions,including, for example, sterile solutions of water for injection (WFI),saline solution, dextrose solution, Hank's solution, Ringer's solution,vegetable oils, mineral oils, animal oils, polyethylene glycols, liquidparaffin, and the like. Excipients may also include, for example,colloidal silicon dioxide, silica gel, talc, magnesium silicate, calciumsilicate, sodium aluminosilicate, magnesium trisilicate, powderedcellulose, macrocrystalline cellulose, carboxymethyl cellulose,cross-linked sodium carboxymethylcellulose, sodium benzoate, calciumcarbonate, magnesium carbonate, stearic acid, aluminum stearate, calciumstearate, magnesium stearate, zinc stearate, sodium stearyl fumarate,syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate,glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate,hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seedoil mineral oil, polyethylene glycol (e.g. PEG 4000-8000),polyoxyethylene glycol, poloxamers, povidone, crospovidone,croscarmellose sodium, alginic acid, casein, methacrylic aciddivinylbenzene copolymer, sodium docusate, cyclodextrins (e.g.2-hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000succinate), magnesium lauryl sulfate, sodium lauryl sulfate,polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols,or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylenesorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters,sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fattyacid such as oleic, stearic or palmitic acid, mannitol, xylitol,sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried,sucrose, fructose, calcium phosphate, dibasic calcium phosphate,tribasic calcium phosphate, calcium sulfate, dextrates, dextran,dextrin, dextrose, cellulose acetate, maltodextrin, simethicone,polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcelluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, andthe like.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the invention(as a free-base, solvate (including hydrate) or salt, in any form),depending on the condition being treated, the route of administration,and the age, weight and condition of the patient. Preferred unit dosageformulations are those containing a daily dose, weekly dose, monthlydose, a sub-dose or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including capsules, tablets,liquid-filled capsules, disintegrating tablets, immediate, delayed andcontrolled release tablets, oral strips, solutions, syrups, buccal andsublingual), rectal, nasal, inhalation, topical (including transdermal),vaginal or parenteral (including subcutaneous, intramuscular,intravenous or intradermal) route. Such formulations may be prepared byany method known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s), excipient(s) ordiluent. Generally, the carrier, excipient or diluent employed in thepharmaceutical formulation is “non-toxic,” meaning that it/they is/aredeemed safe for consumption in the amount delivered in thepharmaceutical composition, and “inert” meaning that it/they does/do notappreciably react with or result in an undesired effect on thetherapeutic activity of the active ingredient.

In some embodiments, oral administration may be used. Pharmaceuticalpreparations for oral use can be formulated into conventional oraldosage forms such as discret units capsules, tablets, and liquidpreparations such as syrups, elixirs, and concentrated drops. Compoundsdescribed herein may be combined with solid excipients, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain, for example,tablets, coated tablets, hard capsules, soft capsules, solutions (e.g.aqueous, alcoholic, or oily solutions) and the like. Suitable excipientsare, in particular, fillers such as sugars, including lactose, glucose,sucrose, mannitol, or sorbitol; cellulose preparations, for example,corn starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP:povidone); oily excipients, including vegetable and animal oils, such assunflower oil, olive oil, or codliver oil. The oral dosage formulationsmay also contain disintegrating agents, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such assodium alginate; a lubricant, such as talc or magnesium stearate; aplasticizer, such as glycerol or sorbitol; a sweetening such as sucrose,fructose, lactose, or aspartame; a natural or artificial flavoringagent, such as peppermint, oil of wintergreen, or cherry flavoring; ordye-stuffs or pigments, which may be used for identification orcharacterization of different doses or combinations, such as unitdosages. Also provided are dragee cores with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Oral fluids such assolutions, syrups and elixirs can be prepared in dosage unit form sothat a given quantity contains a predetermined amount of the compound.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols.

In some embodiments, injection (parenteral administration) may be used,e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous.Compounds described herein for injection may be formulated in sterileliquid solutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. Dispersions may also be prepared in non-aqueous solutions,such as glycerol, propylene glycol, ethanol, liquid polyethyleneglycols, triacetin, and vegetable oils. Solutions may also contain apreservative, such as methylparaben, propylparaben, chlorobutanol,phenol, sorbic acid, thimerosal, and the like. In addition, thecompounds may be formulated in solid form, including, for example,lyophilized forms, and redissolved or suspended prior to use. Theformulations may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example water for injection, immediately prior touse.

In some embodiments, transmucosal, topical or transdermal administrationmay be used. In such formulations of compounds described herein,penetrants appropriate to the barrier to be permeated are used. Suchpenetrants are generally known in the art, and include, for example, fortransmucosal administration, bile salts and fusidic acid derivatives. Inaddition, detergents may be used to facilitate permeation. Transmucosaladministration, for example, may be through nasal sprays orsuppositories (rectal or vaginal). Compositions of compounds describedherein for topical administration may be formulated as oils, creams,lotions, ointments, and the like by choice of appropriate carriers knownin the art. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). In someembodiments, carriers are selected such that the active ingredient issoluble. Emulsifiers, stabilizers, humectants and antioxidants may alsobe included as well as agents imparting color or fragrance, if desired.Creams for topical application are preferably formulated from a mixtureof mineral oil, self-emulsifying beeswax and water in which mixture theactive ingredient, dissolved in a small amount of solvent (e.g., anoil), is admixed. Additionally, administration by transdermal means maycomprise a transdermal patch or dressing such as a bandage impregnatedwith an active ingredient and optionally one or more carriers ordiluents known in the art. To be administered in the form of atransdermal delivery system, the dosage administration will becontinuous rather than intermittent throughout the dosage regimen.

In some embodiments, compounds are administered as inhalants. Compoundsdescribed herein may be formulated as dry powder or a suitable solution,suspension, or aerosol. Powders and solutions may be formulated withsuitable additives known in the art. For example, powders may include asuitable powder base such as lactose or starch, and solutions maycomprise propylene glycol, sterile water, ethanol, sodium chloride andother additives, such as acid, alkali and buffer salts. Such solutionsor suspensions may be administered by inhaling via spray, pump,atomizer, or nebulizer, and the like. The compounds described herein mayalso be used in combination with other inhaled therapies, for examplecorticosteroids such as fluticasone proprionate, beclomethasonedipropionate, triamcinolone acetonide, budesonide, and mometasonefuroate; beta agonists such as albuterol, salmeterol, and formoterol;anticholinergic agents such as ipratroprium bromide or tiotropium;vasodilators such as treprostinal and iloprost; enzymes such as DNAase;therapeutic proteins; immunoglobulin antibodies; an oligonucleotide,such as single or double stranded DNA or RNA, siRNA; antibiotics such astobramycin; muscarinic receptor antagonists; leukotriene antagonists;cytokine antagonists; protease inhibitors; cromolyn sodium; nedocrilsodium; and sodium cromoglycate.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundactivity (in vitro, e.g. the compound IC₅₀ vs. target, or in vivoactivity in animal efficacy models), pharmacokinetic results in animalmodels (e.g. biological half-life or bioavailability), the age, size,and weight of the subject, and the disorder associated with the subject.The importance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be in the range ofabout 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject beingtreated. Multiple doses may be used.

The compounds described herein may also be used in combination withother therapies for treating the same disease. Such combination useincludes administration of the compounds and one or more othertherapeutics at different times, or co-administration of the compoundand one or more other therapies. In some embodiments, dosage may bemodified for one or more of the compounds of the invention or othertherapeutics used in combination, e.g., reduction in the amount dosedrelative to a compound or therapy used alone, by methods well known tothose of ordinary skill in the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than acompound described herein, or at the same time as a compound describedherein. Use in combination also includes use with a therapy or medicalprocedure that is administered once or infrequently, such as surgery,along with a compound described herein administered within a short timeor longer time before or after the other therapy or procedure. In someembodiments, the present invention provides for delivery of a compounddescribed herein and one or more other drug therapeutics delivered by adifferent route of administration or by the same route ofadministration. The use in combination for any route of administrationincludes delivery of a compound described herein and one or more otherdrug therapeutics delivered by the same route of administration togetherin any formulation, including formulations where the two compounds arechemically linked in such a way that they maintain their therapeuticactivity when administered. In one aspect, the other drug therapy may beco-administered with a compound described herein. Use in combination byco-administration includes administration of co-formulations orformulations of chemically joined compounds, or administration of two ormore compounds in separate formulations within a short time of eachother (e.g. within an hour, 2 hours, 3 hours, up to 24 hours),administered by the same or different routes. Co-administration ofseparate formulations includes co-administration by delivery via onedevice, for example the same inhalant device, the same syringe, etc., oradministration from separate devices within a short time of each other.Co-formulations of a compound described herein and one or moreadditional drug therapies delivered by the same route includespreparation of the materials together such that they can be administeredby one device, including the separate compounds combined in oneformulation, or compounds that are modified such that they arechemically joined, yet still maintain their biological activity. Suchchemically joined compounds may have a linkage that is substantiallymaintained in vivo, or the linkage may break down in vivo, separatingthe two active components.

V. Kinase Targets and Indications of the Invention

Protein kinases play key roles in propagating biochemical signals indiverse biological pathways.

More than 500 kinases have been described, and specific kinases havebeen implicated in a wide range of diseases or conditions (i.e.,indications), including for example without limitation, cancer,cardiovascular disease, inflammatory disease, neurological disease, andother diseases. As such, kinases represent important control points forsmall molecule therapeutic intervention. Specific target protein kinasescontemplated by the present invention are described in the art,including, without limitation, protein kinases as described in U.S.patent application Ser. No. 11/473,347 (see also, PCT publicationWO2007002433), the disclosure of which is hereby incorporated byreference as it relates to such kinase targets, as well as thefollowing:

A-Raf: Target kinase A-Raf (i.e., v-raf murine sarcoma 3611 viraloncogene homolog 1) is a 67.6 kDa serine/threonine kinase encoded bychromosome Xp11.4-p11.2 (symbol: ARAF). The mature protein comprises RBD(i.e., Ras binding domain) and phorbol-ester/DAG-type zinc finger domainand is involved in the transduction of mitogenic signals from the cellmembrane to the nucleus. A-Raf inhibitors may be useful in treatingneurologic diseases such as multi-infarct dementia, head injury, spinalcord injury, Alzheimer's disease (AD), Parkinson's disease; neoplasticdiseases including, but not limited to, melanoma, glioma, sarcoma,carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal,ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis,myelodysplastic syndrome, leukemia, tumor angiogenesis; pain ofneuropathic or inflammatory origin, including acute pain, chronic pain,cancer-related pain and migraine; and diseases associated with muscleregeneration or degeneration, including, but not limited to, vascularrestenosis, sarcopenia, muscular dystrophies (including, but not limitedto, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral,Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies),motor neuron diseases (including, but not limited to, amyotrophiclateral sclerosis, infantile progressive spinal muscular atrophy,intermediate spinal muscular atrophy, juvenile spinal muscular atrophy,spinal bulbar muscular atrophy, and adult spinal muscular atrophy),inflammatory myopathies (including, but not limited to, dermatomyositis,polymyositis, and inclusion body myositis), diseases of theneuromuscular junction (including, but not limited to, myastheniagravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome),myopathies due to endocrine abnormalities (including, but not limitedto, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogenehomolog B1) is a 84.4 kDa serine/threonine kinase encoded by chromosome7q34 (symbol: BRAF). The mature protein comprises RBD (i.e., Ras bindingdomain), C1 (i.e., protein kinase C conserved region 1) and STK (i.e.,serine/threonine kinase) domains.

Target kinase B-Raf is involved in the transduction of mitogenic signalsfrom the cell membrane to the nucleus and may play a role in thepostsynaptic responses of hippocampal neurons. As such, genes of the RAFfamily encode kinases that are regulated by Ras and mediate cellularresponses to growth signals. Indeed, B-Rafkinase is a key component ofthe RAS->Raf->MEK->ERK/MAP kinase signaling pathway, which plays afundamental role in the regulation of cell growth, division andproliferation, and, when constitutively activated, causes tumorigenesis.Among several isoforms of Raf kinase, the B-type, or B-Raf, is thestrongest activator of the downstream MAP kinase signaling.

The BRAF gene is frequently mutated in a variety of human tumors,especially in malignant melanoma and colon carcinoma. The most commonreported mutation was a missense thymine (T) to adenine (A) transversionat nucleotide 1796 (T1796A; amino acid change in the B-Raf protein isVal<600> to Glu<600>) observed in 80% of malignant melanoma tumors.Functional analysis reveals that this transversion is the only detectedmutation that causes constitutive activation of B-Raf kinase activity,independent of RAS activation, by converting B-Raf into a dominanttransforming protein. Based on precedents, human tumors developresistance to kinase inhibitors by mutating a specific amino acid in thecatalytic domain as the “gatekeeper”. (Balak, et. al., Clin Cancer Res.2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thusanticipated as a mechanism of resistance to BRAF inhibitors, and thiscan be envisioned as a transition in codon 529 from ACC to ATC.

Niihori et al., report that in 43 individuals withcardio-facio-cutaneous (CFC) syndrome, they identified two heterozygousKRAS mutations in three individuals and eight BRAF mutations in 16individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway isa common molecular basis for the three related disorders (Niihori etal., Nat Genet. 2006, 38(3):294-6).

Many cancers associated with dysregulation of the RAS-RAF-ERK pathway,such as cancers having B-Raf V600, such as V600E mutations or NRASmutations, may be treated with Raf kinase inhibitors, such as the PanRafkinase inhibitors as described herein. The ability of these compoundsto inhibit multiple Raf kinase targets, including c-Raf-1, B-Raf, andB-Raf V600, such as V600E, provides additional benefits for inhibitingactivating mutations in this pathway, with such cancers less likely todevelop resistance to such inhibitors as they are targeting severalpoints in the pathway. Pan Raf kinase inhibitors as described herein maybe useful in treating a variety of cancers, including, but not limitedto, melanoma, glioma, glioblastoma mulitforme, pilocytic astrocytoma,carcinoma (e.g. gastrointestinal, liver, biliary tract, bile duct(cholangiocarcinoma), colorectal, lung, brain, bladder, gallbladder,breast, pancreatic, thyroid, kidney, ovarian, adrenocortical, prostate),gastrointestinal stromal tumors, medullary thyroid cancer, tumorangiogenesis, acute myeloid leukemia, chronic myelomonocytic leukemia,childhood acute lymphoblastic leukemia, plasma cell leukemia, andmultiple myeloma. See McDermott et al., PNAS, 2007, 104(50):19936-19941; and Jaiswal et al., PLoS One, 2009, 4(5):e5717.

c-Raf-1: Target kinase c-Raf-1 (i.e., v-rafmurine sarcoma viral oncogenehomolog 1) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAFI).c-Raf-1 can be targeted to the mitochondria by BCL2 (i.e., oncogeneB-cell leukemia 2) which is a regulator of apoptotic cell death. Activec-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1phosphorylates BAD (i.e., BCL2-binding protein). c-Raf-1 is implicatedin carcinomas, including colorectal, ovarian, lung and renal cellcarcinoma. c-Raf-1 is also implicated as an important mediator of tumorangiogenesis (Hood, J. D. et al., 2002, Science 296, 2404). c-Raf-1inhibitors may also be useful for the treatment of acute myeloidleukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002,8(25):2243-8). c-Raf-1 activators may be useful as treatment forneuroendocrine tumors, such as medullary thyroid cancer, carcinoid,small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al.,Anticancer Drugs 2006, 17(2):139-42).

Raf inhibitors (A-Raf and/or B-Raf and/or c-Raf-1) may be useful intreating A-Raf-mediated, B-Raf-mediated or c-Raf-1-mediated diseases orconditions selected from the group consisting of neurologic diseases,including, but not limited to, multi-infarct dementia, head injury,spinal cord injury, Alzheimer's disease (AD), Parkinson's disease,seizures and epilepsy; neoplastic diseases including, but not limitedto, melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,sarcoma, carcinoma (e.g. gastrointestinal, liver, biliary tract, bileduct (cholangiocarcinoma), colorectal, lung, brain, bladder,gallbladder, breast, pancreatic, thyroid, renal, ovarian,adrenocortical, prostate), lymphoma (e.g. histiocytic lymphoma)neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome,leukemia, chronic myelomonocytic leukemia, childhood, acutelymphoblastic leukemia, plasma cell leukemia, multiple myeloma, tumorangiogenesis, gastrointestinal stromal tumors, neuroendocrine tumorssuch as medullary thyroid cancer, carcinoid, small cell lung cancer,Kaposi's sarcoma, and pheochromocytoma; pain of neuropathic orinflammatory origin, including, but not limited to, acute pain, chronicpain, cancer-related pain, and migraine; cardiovascular diseasesincluding, but not limited to, heart failure, ischemic stroke, cardiachypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes),atherosclerosis, and reperfusion injury; inflammation and/orproliferation including, but not limited to, psoriasis, eczema,arthritis and autoimmune diseases and conditions, osteoarthritis,endometriosis, scarring, vascular restenosis, fibrotic disorders,rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiencydiseases, including, but not limited to, organ transplant rejection,graft versus host disease, and Kaposi's sarcoma associated with HIV;renal, cystic, or prostatic diseases, including, but not limited to,diabetic nephropathy, polycystic kidney disease, nephrosclerosis,glomerulonephritis, prostate hyperplasia, polycystic liver disease,tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidneydisease, nephronophthisis, and cystic fibrosis; metabolic disorders,including, but not limited to, obesity; infection, including, but notlimited to Helicobacter pylori, Hepatitis and Influenza viruses, fever,HIV, and sepsis; pulmonary diseases including, but not limited to,chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to, Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;and diseases associated with muscle regeneration or degeneration,including, but not limited to, sarcopenia, muscular dystrophies(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal andCongenital Muscular Dystrophies), motor neuron diseases (including, butnot limited to, amyotrophic lateral sclerosis, infantile progressivespinal muscular atrophy, intermediate spinal muscular atrophy, juvenilespinal muscular atrophy, spinal bulbar muscular atrophy, and adultspinal muscular atrophy), inflammatory myopathies (including, but notlimited to, dermatomyositis, polymyositis, and inclusion body myositis),diseases of the neuromuscular junction (including, but not limited to,myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenicsyndrome), myopathies due to endocrine abnormalities (including, but notlimited to, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency).

Erk2: Target kinase Erk2 (i.e., extracellular signal-regulated kinase 2)is a 41.4 kDa dual function serine/threonine-tyrosine kinase encoded bychromosome 22q11.2 (symbol: MAPK1). Erk2 is a member of themitogen-activated protein (MAP) kinase family and is alternatively knownas mitogen-activated protein kinase 1 (i.e., MAPK1). MAP kinases act asan integration point for multiple biochemical signals, and are involvedin a wide variety of cellular processes such as proliferation,differentiation, transcription regulation and development.

The activation of Erk2 requires phosphorylation by upstream kinases.Upon activation, Erk2 translocates to the nucleus of the stimulatedcells, where it phosphorylates nuclear targets, in addition to othertargets including microtubule associated protein 2, myelin basic proteinand ELK1. MacKenzie et al. state that the cAMP-specificphosphodiesterase family 4, subfamily D, isoform 3 (i.e., PDE4D3) isshown to have FQF (i.e., Phe-Gln-Phe) and KIM (i.e., Kinase InteractionMotif) docking sites for Erk2. These sites straddle the Ser(579) targetresidue for Erk2 phosphorylation of PDE4D3. Mutation of either or bothof these docking sites prevent Erk2 from being co-immunoprecipitatedwith PDE4D3, ablate the ability of epidermal growth factor (EGF) toinhibit PDE4D3 through Erk2 action in transfected COS cells, andattenuate the ability of Erk2 to phosphorylate PDE4D3 in vitro. The twoconserved NH(2)-terminal blocks of sequence, called upstream conservedregions 1 and 2 (i.e., UCR1 and UCR2), that characterize PDE4 longisoforms, are proposed to amplify the small, inherent inhibitory effectthat Erk2 phosphorylation exerts on the PDE4D catalytic unit. Incontrast to this, the lone intact UCR2 region found in PDE4D1 directsCOOH-terminal Erk2 phosphorylation to cause the activation of this shortisoform. From the analysis of PDE4D3 truncates, it is suggested thatUCR1 and UCR2 provide a regulatory signal integration module that servesto orchestrate the functional consequences of Erk2 phosphorylation. ThePDE4D gene thus encodes a series of isoenzymes that are either inhibitedor activated by Erk2 phosphorylation and thereby offers the potentialfor ERK2 activation either to increase or decrease cAMP levels incellular compartments (MacKenzie et al., J Biol Chem 2000, 275(22):16609-17).

According to OMIM, Pleschka et al. (Nature Cell Biol., 2001, 3: 301-305)proposed that Erk2 regulates a cellular factor involved in the viralnuclear export protein function. They suggested that local applicationof MEK inhibitors may have only minor toxic effects on the host whileinhibiting viral replication without giving rise to drug-resistant virusvariants (OMIM MIM Number: 176948: Oct. 27, 2005). Erk2 is involved incytokine signaling and is a target for treating inflammation. Ramesh andPhilipp state that lipoproteins are the key inflammatory molecule typeof Borrelia burgdorferi, the spirochete that causes Lyme disease. Theyinvestigated whether specific inhibition of p38 and Erk1/2 MAPK wouldinhibit TNF-alpha and IL-6 production and thus astrocyte apoptosis, andproliferation, respectively. Lipoprotein-stimulated IL-6 production wasunaffected by the MAPK inhibitors. In contrast, inhibition of both p38and Erk1/2 significantly diminished TNF-alpha production, and totallyabrogated production of this cytokine when both MAPK pathways wereinhibited simultaneously. MAPK inhibition thus may be considered as astrategy to control inflammation and apoptosis in Lyme neuroborreliosis(Ramesh and Philipp, Neurosci Lett 2005, 384(1-2):112-6). The role ofErk2 in signaling of cell differentiation, proliferation and survivalsuggests that inhibition of Erk2 may be therapeutic for several types ofcancer. Husain et al. studied the effect of NSAIDs on MAPK activity andphosphorylation in gastric cancer. They conclude that NS-398 (aselective COX-2 inhibitor) and indomethacin (a non-selective NSAID)significantly inhibit proliferation and growth of human gastric cancercell line MKN28. This effect is mediated by NSAID-induced inhibition ofMAPK (ERK2) kinase signaling pathway, essential for cell proliferation(Husain et al., Life Sci 2001, 69(25-6):3045-54). Erk2 inhibitors may beuseful in treating cancer, including gastric cancer, and in treatinginflammation, including control of inflammation and apoptosis in Lymeneuroborreliosis.

Kinase Activity Assays

A number of different assays for kinase activity can be utilized forassaying for active modulators and/or determining specificity of amodulator for a particular kinase or group or kinases. In addition tothe assay mentioned in the Examples below, one of ordinary skill in theart will know of other assays that can be utilized and can modify anassay for a particular application. For example, numerous papersconcerning kinases describe assays that can be used.

In certain embodiments, compounds as disclosed herein are active in anassay measuring B-Raf protein kinase activity. In some embodiments, acompound as described herein has an IC₅₀ of less than 1,000 nM, lessthan 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted B-Rafkinase activity assay. In some embodiments, acompound as described herein has an IC₅₀ of less than 1,000 nM, lessthan 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted mutant B-Rafkinase (such as V600A, V600M, V600R,V600E, V600K or V600G) activity assay. In some embodiments the assay formeasuring B-Raf kinase activity and/or mutant B-Raf kinase (such asV600A, V600M, V600R, V600E, V600K or V600G) activity includes an assay(e.g., biochemical or cell-bases assays) such as described in Example 9or an assay well known in the art similar to those described in Example9.

In some embodiments, compounds as described herein have little or noactivity in an assay measuring activation of the ERK pathway (i.e., instimulating the phosphorylation of ERK 1/2). In some embodiments,compounds as described herein have an EC₅₀ in an ERK activation assaythat is greater than 1 μM; or greater than 2 μM; or greater than 3 μM;or greater than 4 μM; or greater than 5 μM; or greater than 8 μM; orgreater than 10 μM. In certain embodiments, the assay for measuringactivation of the ERK pathway includes an assay (e.g., biochemical orcell-bases assays) such as described in Example 9 or one or more assayswell known in the art for measuring ERK activity similar to thatdescribed in Example 9.

In some embodiments, compounds as described herein are active in anassay measuring B-Raf protein kinase activity and/or an assay formeasuring mutant B-Raf (such as V600A, V600M, V600R, V600E, V600K orV600G) protein kinase activity, and have little or no activity in anassay measuring activation of the ERK pathway. In some embodiments acompound as described herein has an IC₅₀ of less than 1,000 nM, lessthan 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, lessthan 10 nM, less than 5 nM, or less than 1 nM as determined in agenerally accepted B-Raf kinase activity assay (including a mutant B-Rafkinase activity assay) and an EC₅₀ in an ERK activation assay that isgreater than 1 μM; or greater than 2 μM; or greater than 3 μM; orgreater than 4 μM; or greater than 5 μM; or greater than 8 μM; orgreater than 10 μM. In some embodiments, a compound as described hereinhas an IC₅₀ of less than 100 nM in a V600A, V600M, V600R, V600E, V600Kor V600G mutant B-Raf activity assay and an EC₅₀ of greater than 10 inan ERK activation assay.

VI. Methods for Treating Conditions Mediated by Kinases

In another aspect, the present invention provides a method for treatinga subject suffering from or at risk of a protein kinase mediateddiseases or conditions. The method includes administering to the subjectan effective amount of a compound of any of formulas I and Ia to In, ora compound as described herein, or a composition comprising any offormulas I and Ia to In and any of the compounds described herein or apharmaceutically acceptable salt or a solvate or hydrate thereof. Incertain embodiments, the method involves administering to the subject aneffective amount of any one or more compound(s) as described herein incombination with one or more other therapies for the disease orcondition.

In some embodiments, the diseases or conditions treatable with thecompounds of the present invention include, but are not limited to,multi-infarct dementia, head injury, spinal cord injury, Alzheimer'sdisease (AD), Parkinson's disease, seizures and epilepsy; neoplasticdiseases including, but not limited to, melanoma, glioma, glioblastomamultiforme, pilocytic astrocytoma, sarcoma, carcinoma (e.g.gastrointestinal, liver, biliary tract, bile duct (cholangiocarcinoma),colorectal, lung, gallbladder, breast, pancreatic, thyroid, renal,ovarian, adrenocortical, prostate), lymphoma (e.g. histiocytic lymphoma)neurofibromatosis, gastrointestinal stromal tumors, acute myeloidleukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis,neuroendocrine tumors such as medullary thyroid cancer, carcinoid, smallcell lung cancer, Kaposi's sarcoma, and pheochromocytoma; pain ofneuropathic or inflammatory origin, including, but not limited to, acutepain, chronic pain, cancer-related pain, and migraine; cardiovasculardiseases including, but not limited to, heart failure, ischemic stroke,cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathysyndromes), atherosclerosis, and reperfusion injury; inflammation and/orproliferation including, but not limited to, psoriasis, eczema,arthritis and autoimmune diseases and conditions, osteoarthritis,endometriosis, scarring, vascular restenosis, fibrotic disorders,rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiencydiseases, including, but not limited to, organ transplant rejection,graft versus host disease, and Kaposi's sarcoma associated with HIV;renal, cystic, or prostatic diseases, including, but not limited to,diabetic nephropathy, polycystic kidney disease, nephrosclerosis,glomerulonephritis, prostate hyperplasia, polycystic liver disease,tuberous sclerosis, Von Hippel Lindau disease, medullary cystic kidneydisease, nephronophthisis, and cystic fibrosis; metabolic disorders,including, but not limited to, obesity; infection, including, but notlimited to Helicobacter pylori, Hepatitis and Influenza viruses, fever,HIV, and sepsis; pulmonary diseases including, but not limited to,chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS); genetic developmental diseases, including, butnot limited to, Noonan's syndrome, Costello syndrome,(faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneoussyndrome (CFC), and neural crest syndrome abnormalities causingcardiovascular, skeletal, intestinal, skin, hair and endocrine diseases;and diseases associated with muscle regeneration or degeneration,including, but not limited to, sarcopenia, muscular dystrophies(including, but not limited to, Duchenne, Becker, Emery-Dreifuss,Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal andCongenital Muscular Dystrophies), motor neuron diseases (including, butnot limited to, amyotrophic lateral sclerosis, infantile progressivespinal muscular atrophy, intermediate spinal muscular atrophy, juvenilespinal muscular atrophy, spinal bulbar muscular atrophy, and adultspinal muscular atrophy), inflammatory myopathies (including, but notlimited to, dermatomyositis, polymyositis, and inclusion body myositis),diseases of the neuromuscular junction (including, but not limited to,myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenicsyndrome), myopathies due to endocrine abnormalities (including, but notlimited to, hyperthyroid myopathy and hypothyroid myopathy) diseases ofperipheral nerve (including, but not limited to, Charcot-Marie-Toothdisease, Dejerine-Sottas disease, and Friedreich's ataxia), othermyopathies (including, but not limited to, myotonia congenita,paramyotonia congenita, central core disease, nemaline myopathy,myotubular myopathy, and periodic paralysis), and metabolic diseases ofmuscle (including, but not limited to, phosphorylase deficiency, acidmaltase deficiency, phosphofructokinase deficiency, debrancher enzymedeficiency, mitochondrial myopathy, carnitine deficiency, carnitinepalmatyl transferase deficiency, phosphoglycerate kinase deficiency,phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency,and myoadenylate deaminase deficiency). In one embodiment, the diseaseor condition is selected from the group consisting of melanoma, glioma,glioblastoma multiforme, pilocytic astrocytoma, sarcoma, liver cancer,biliary tract cancer, cholangiocarcinoma, colorectal cancer, lungcancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroidcancer, renal cancer, ovarian cancer, adrenocortical cancer, prostatecancer, histiocytic lymphoma, neurofibromatosis, gastrointestinalstromal tumors, acute myeloid leukemia, myelodysplastic syndrome,leukemia, tumor angiogenesis, medullary thyroid cancer, carcinoid, smallcell lung cancer, Kaposi's sarcoma, pheochromocytoma, acute pain,chronic pain, and polycystic kidney disease. In a preferred embodiment,the disease or condition is selected from the group consisting ofmelanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma,colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostatecancer, liver cancer, gallbladder cancer, gastrointestinal stromaltumors, biliary tract cancer, cholangiocarcinoma, acute pain, chronicpain, and polycystic kidney disease.

In other embodiments, the diseases or condictions treatable with thecompounds of the present invention include, but are not limited to,ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, headinjury, spinal cord injury, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis, dementia, senile chorea, Huntington'sdisease, neoplastic disease, complications with neoplastic disease,chemotherapy-induced hypoxia, gastrointestinal stromal tumors, prostatetumors, mast cell tumors, canine mast cell tumors, acute myeloidleukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chroniclymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, glioma,glioblastoma, astrocytoma, neuroblastoma, sarcomas, sarcomas ofneuroectodermal origin, leiomyosarcoma, lung carcinoma, breastcarcinoma, pancreatic carcinoma, colon carcinoma, hepatocellularcarcinoma, renal carcinoma, carcinoma of the female genital tract,squamous cell carcinoma, carcinoma in situ, lymphoma, histiocyticlymphoma, non-Hodgkin's lymphoma, MEN2 syndromes, neurofibromatosis,Schwann cell neoplasia, myelodysplastic syndrome, leukemia, tumorangiogenesis, thyroid cancer, liver cancer, bone cancer, skin cancer,brain cancer, cancer of the central nervous system, pancreatic cancer,lung cancer, small cell lung cancer, non small cell lung cancer, breastcancer, colon cancer, bladder cancer, prostate cancer, gastrointestinaltract cancer, cancer of the endometrium, fallopian tubecancer,testicular cancer, ovarian cancer, pain of neuropathic origin, pain ofinflammatory origin, acute pain, chronic pain, migraine, cardiovasculardisease, heart failure, cardiac hypertrophy, thrombosis, thromboticmicroangiopathy syndromes, atherosclerosis, reperfusion injury,ischemia, cerebrovascular ischemia, liver ischemia, inflammation,polycystic kidney disease, age-related macular degeneration, rheumatoidarthritis, allergic rhinitis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, systemic lupus erythematosis, Sjogren'sSyndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronicthyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis,osteoarthritis, endometriosis, dermal scarring, tissue scarring,vascular restenosis, fibrotic disorders, hypereosinophilia, CNSinflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis,immunodeficiency diseases, severe combined immunodeficiency, organtransplant rejection, graft versus host disease, renal disease,prostatic disease, diabetic nephropathy, nephrosclerosis,glomerulonephritis, interstitial nephritis, Lupus nephritis, prostatehyperplasia, chronic renal failure, tubular necrosis,diabetes-associated renal complication, associated renal hypertrophy,type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepaticsteatosis, insulin resistance, hyperglycemia, lipolysis obesity,infection, Helicobacter pylori infection, Influenza virus infection,fever, sepsis, pulmonary diseases, chronic obstructive pulmonarydisease, acute respiratory distress syndrome, asthma, allergy,bronchitis, emphysema, pulmonary fibrosis, genetic developmentaldiseases, Noonan's syndrome, Crouzon syndrome, acrocephalo-syndactylytype I, Pfeiffer's syndrome, Jackson-Weiss syndrome, Costello syndrome,faciocutaneoskeletal syndrome, leopard syndrome, cardio-faciocutaneoussyndrome, neural crest syndrome abnormalities causing cardiovascular,skeletal, intestinal, skin, hair or endocrine diseases, disorders ofbone structure or mineralization, osteoporosis, increased risk offracture, hypercalcemia, bone metastases, Grave's disease,Hirschsprung's disease, lymphoedema, selective T-cell defect, X-linkedagammaglobulinemia, diabetic retinopathy, alopecia, erectiledysfunction, and tuberous sclerosis

In some embodiments, the disease is a cancer selected from the groupconsisting of melanoma, glioma, glioblastoma, pilocytic astrocytoma,liver cancer, biliary tract cancer, cholangiocarcinoma, colorectalcancer, lung cancer, bladder cancer, gallbladder cancer, breast cancer,pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer,adrenocortical cancer, prostate cancer, gastrointestinal stromal tumors,medullary thyroid cancer, tumor angiogenesis, acute myeloid leukemia,chronic myelomonocytic leukemia, childhood acute lymphoblastic leukemia,plasma cell leukemia, and multiple myeloma. In certain instances, thedisease is a B-RafV600, such as V600A, V600E, V600G, V600K, V600M orV600R mutant-mediated disease. In one embodiment, the disease is a V600Emutant mediated disease. In one embodiment, the disease is a cancer,preferably selected from the group consisting of melanoma, glioma,glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer,thyroid cancer, lung cancer, ovarian cancer, prostate cancer, livercancer, gallbladder cancer, gastrointestinal stromal tumors, biliarytract cancer, and cholangiocarcinoma. In one embodiment, the cancer ismelanoma, colorectal cancer, thyroid cancer or lung cancer.

In some embodiments, the invention provides methods for treating anyB-Raf protein kinase mediated disease or condition, including any B-Rafmutant kinase mediated disease or condition in an animal subject in needthereof, wherein the method involves administering to the subject aneffective amount of any one or more compound(s) as described herein. Incertain embodiments, the method involves administering to the subject aneffective amount of any one or more compound(s) as described herein incombination with one or more other therapies for the disease orcondition.

In some embodiments, the invention provides methods for treating anyB-Raf V600 mutant protein kinase, such as V600A, V600E, V600G, V600K,V600M or V600R mutant protein kinase mediated disease or condition in ananimal subject in need thereof, wherein the method involvesadministering to the subject an effective amount of any one or morecompound(s) as described herein. In certain embodiments, the methodinvolves administering to the subject an effective amount of any one ormore compound(s) as described herein in combination with one or moreother therapies for the disease or condition.

In some embodiments, a compound as described herein is a Rafkinaseinhibitor and has an IC₅₀ of less than 500 nM, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a generally accepted Rafkinase activityassay. In some embodiments, a compound as described herein will have anIC₅₀ of less than 500 nM, less than 100 nM, less than 50 nM, less than20 nM, less than 10 nM, less than 5 nM, or less than 1 nM with respectto B-Raf, c-Raf-1, or B-RafV600E mutant. In some embodiments, a compoundas described herein will selectively inhibit one or more Raf kinasesrelative to one or more other Raf kinases.

In some embodiments, the invention provides a method for inhibiting aB-Raf V600 mutant protein kinase, such as V600A, V600E, V600G, V600K,V600M or V600R mutant protein kinase. The method includes contacting acompound of any of formulas I and Ia to In, or a compound as describedherein, or a composition comprising any of formulas I and Ia to In andany of the compounds described herein or a pharmaceutically acceptablesalt or a solvate thereof with a cell or a B-Raf V600 mutant proteinkinase either in vitro or in vivo.

In certain embodiments, the invention provides use of a compound of anyof formulas I and Ia to In, or a compound as described herein, or acomposition comprising any of formulas I and Ia to In and any of thecompounds described herein or a pharmaceutically acceptable salt or asolvate thereof in the manufacture of a medicament for the treatment ofa disease or condition as described herein. In other embodiments, theinvention provides a compound of any of formulas I and Ia to In, or acompound as described herein, or a composition comprising any offormulas I and Ia to In and any of the compounds described herein or apharmaceutically acceptable salt or a solvate thereof for use intreating a disease or condition as described herein.

In some embodiments, the invention provides a method for suppressing UVinduced cell apoptosis. The method includes contacting a cell with acompound of any of formulas I and Ia to In, or a compound as describedherein, or a composition comprising any of formulas I and Ia to In andany of the compounds described herein or a pharmaceutically acceptablesalt or a solvate thereof prior to subject the cell to UV exposure orradiation.

Combination Therapy

Protein kinase modulators may be usefully combined with anotherpharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofcancer. In one embodiment, the composition includes any one or morecompound(s) as described herein along with one or more compounds thatare therapeutically effective for the same disease indication, whereinthe compounds have a synergistic effect on the disease indication. Inone embodiment, the composition includes any one or more compound(s) asdescribed herein effective in treating a cancer and one or more othercompounds that are effective in treating the same cancer, furtherwherein the compounds are synergistically effective in treating thecancer.

In some embodiments, the invention provides a composition comprising acompound of any of formula (I) and formula Ia to formula In, or acompound described herein, or a pharmaceutically acceptable salt orsolvate thereof, and one or more agents. In some embodiments, the one ormore agents are selected from an alkylating agent, including, but notlimited to, adozelesin, altretamine, bendamustine, bizelesin, busulfan,carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin,cyclophosphamide, dacarbazine, estramustine, etoglucid, fotemustine,hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan,mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine,oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine,satraplatin, semustine, streptozocin, temozolomide, thiotepa,treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate,trofosphamide, and uramustine; an antibiotic, including, but not limitedto, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin,neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, andzorubicin; an antimetabolite, including, but not limited to,aminopterin, azacitidine, azathioprine, capecitabine, cladribine,clofarabine, cytarabine, decitabine, floxuridine, fludarabine,5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate,nelarabine, pemetrexed, azathioprine, raltitrexed, tegafur-uracil,thioguanine, trimethoprim, trimetrexate, and vidarabine; animmunotherapy, including, but not limited to, alemtuzumab, bevacizumab,cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab,tositumomab, trastuzumab, 90 Y ibritumomab tiuxetan, ipilimumab, andtremelimumab; a hormone or hormone antagonist, including, but notlimited to, anastrozole, androgens, buserelin, diethylstilbestrol,exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole,leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; a taxane,including, but not limited to, DJ-927, docetaxel, TPI 287, larotaxel,ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; a retinoid,including, but not limited to, alitretinoin, bexarotene, fenretinide,isotretinoin, and tretinoin; an alkaloid, including, but not limited to,demecolcine, homoharringtonine, vinblastine, vincristine, vindesine,vinflunine, and vinorelbine; an antiangiogenic agent, including, but notlimited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol,lenalidomide, and thalidomide; a topoisomerase inhibitor, including, butnot limited to, amsacrine, belotecan, edotecarin, etoposide, etoposidephosphate, exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; akinase inhibitor, including, but not limited to, axitinib (AG 013736),dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinibmesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib(AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626,UCN-01 (7-hydroxystaurosporine), and vatalanib; a targeted signaltransduction inhibitor including, but not limited to bortezomn,feldanamycin, and rapamycin; a biological response modifier, including,but not limited to, imiquimod, interferon-

and interleukin-2; and other chemotherapeutics, including, but notlimited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1,cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone,lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac,testolactone, tiazofurin, mTOR inhibitors (e.g. temsirolimus,everolimus, deforolimus), PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147,XL765), Cdk4 inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90inhibitors (e.g. tanespimycin) and farnesyltransferase inhibitors (e.g.tipifarnib); MEK inhibitors (e.g., AS703026, AZD6244 (selumetinib),AZD8330, BIX02188, CI1040 (PD184352), D-87503, GSK1120212 (JTP-74057),PD0325901, PD318088, PD98059, PDEA119 (BAY 869766), TAK-733).Preferably, the method of treating a cancer involves administering tothe subject an effective amount of a composition including any one ormore compound(s) as described herein in combination with achemotherapeutic agent selected from capecitabine, 5-fluorouracil,carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38,temozolomide, vinblastine, bevacizumab, cetuximab, interferon-

, interleukin-2, or erlotinib. In some embodiments, a protein kinasemodulator, particularly a compound of any of formula (I) to formula In,or a compound described herein, or a pharmaceutically acceptable salt orsolvate thereof, as defined above, may be administered simultaneously,sequentially or separately in combination with one or more agents asdescribed above.

In one embodiment, the invention provides methods for treating a diseaseor condition mediated by B-Raf kinase, including mutations thereof, byadministering to the subject an effective amount of a compositionincluding any one or more compound(s) as described herein in combinationwith one or more other suitable therapies for treating the disease.

In one embodiment, the invention provides methods for treating a diseaseor condition mediated by B-Raf V600 mutant kinases, such as V600A,V600E, V600G, V600K, V600M or V600R mutant kinase, by administering tothe subject an effective amount of a composition including any one ormore compound(s) as described herein in combination with one or moreother suitable therapies for treating the disease. In one embodiment,the invention provides methods for treating a cancer mediated by B-Rafmutant kinases, such as V600A, V600E, V600G, V600M or V600R mutant byadministering to the subject an effective amount of a compositionincluding any one or more compound(s) as described herein. In oneembodiment, the invention provides methods for treating a cancermediated by B-Raf mutant kinases, such as V600A, V600E, V600G, V600K,V600M or V600R mutant by administering to the subject an effectiveamount of a composition including any one or more compound(s) asdescribed herein in combination with one or more suitable anticancertherapies, such as one or more chemotherapeutic drugs. In one instance,the B-Raf mutant kinase is V600A. In another instance, the B-Raf mutantkinase is V600E. In yet another instance, the B-Raf mutant kinase isV600G. In another instance, the B-Raf mutant kinase is V600K. In anotherinstance, the B-Raf mutant kinase is V600M. In another instance, theB-Raf mutant kinase is V600R.

In one embodiment, the invention provides a method of treating a cancerin a subject in need thereof by administering to the subject aneffective amount of a composition including any one or more compound(s)as described herein in combination with one or more other therapies ormedical procedures effective in treating the cancer. Other therapies ormedical procedures include suitable anticancer therapy (e.g. drugtherapy, vaccine therapy, gene therapy, photodynamic therapy) or medicalprocedure (e.g. surgery, radiation treatment, hyperthermia heating, bonemarrow or stem cell transplant). In one embodiment, the one or moresuitable anticancer therapies or medical procedures is selected fromtreatment with a chemotherapeutic agent (e.g. chemotherapeutic drug),radiation treatment (e.g. x-ray,

-ray, or electron, proton, neutron, or

particle beam), hyperthermia heating (e.g. microwave, ultrasound,radiofrequency ablation), Vaccine therapy (e.g. AFP gene hepatocellularcarcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneicGM-CSF-secretion breast cancer vaccine, dendritic cell peptidevaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encodingMDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy(e.g. aminolevulinic acid, motexafin lutetium), surgery, or bone marrowand stem cell transplantation.

Kit

In another aspect, he invention provides kits that include a compound ofany of formulas (I) to (In) or a compound as described herein orcomposition thereof as described herein. In some embodiments, thecompound or composition is packaged, e.g., in a vial, bottle, flask,which may be further packaged, e.g., within a box, envelope, or bag; thecompound or composition is approved by the U.S. Food and DrugAdministration or similar regulatory agency for administration to amammal, e.g., a human; the compound or composition is approved foradministration to a mammal, e.g., a human, for a protein kinase mediateddisease or condition; the invention kit may include written instructionsfor use and/or other indication that the compound or composition issuitable or approved for administration to a mammal, e.g., a human, fora Raf protein kinase-mediated disease or condition; and the compound orcomposition may be packaged in unit dose or single dose form, e.g.,single dose pills, capsules, or the like.

VII. Examples

The following examples are offered to illustrate, but not to limit theclaimed invention.

Compounds within the scope of this invention can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisinvention, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest. In some examples, the massspectrometry result indicated for a compound may have more than onevalue due to the isotope distribution of an atom in the molecule, suchas a compound having a bromo or chloro substituent.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1: Preparation of(3-Amino-2,6-difluorophenyl)(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(4)

Synthesis of 2,6-Difluoro-3-nitrobenzoyl chloride (2)

To 2,6-difluoro-3-nitrobenzoic acid (50 g, 246 mmol) was added thionylchloride (185 mL, 2536 mmol). The reaction was heated at 80° C.overnight and allowed to cool to room temperature. The volatiles wereremoved under reduced pressure and then azeotroped from toluene severaltimes to give an oil which was used directly in the next step.

Synthesis of(2,6-Difluoro-3-nitrophenyl)(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(3)

5-Iodo-1H-pyrrolo[2,3-b]pyridine (32.8 g, 134 mmol) and aluminumchloride (108 g, 806 mmol) in nitromethane (340 mL) were allowed to stirat room temperature for 1 hour. Then 2,6-difluoro-3-nitrobenzoylchloride (44.7 g, 202 mmol) in nitromethane (340 mL) was added and themixture was heated at 50° C. for 5 days. After cooling to 0° C., thereaction was quenched with methanol (250 mL) resulting in a ppt. Themixture was diluted with water (500 mL) and then filtered. The crudeproduct which was triturated with ethyl acetate and filtered washingwith additional ethyl acetate to give(2,6-difluoro-3-nitrophenyl)(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(42 g, 98 mmol, 72.8% yield) as a brown solid. ¹H NMR spectrum isconsistent with the structure of the compound.

Synthesis of(3-Amino-2,6-difluorophenyl)(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(4)

To(2,6-difluoro-3-nitrophenyl)(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(44.6 g, 104 mmol) in ethyl acetate (1732 mL) and THF (1732 mL) wastreated portionwise with tin(II) chloride dihydrate (82 g, 364 mmol)while heating 60° C. and held at this temperature overnight. Aftercooling to room temperature, the reaction mixture was quenched with halfsat. aqueous sodium bicarbonate and filtered through Celite washing thecake with ethyl acetate. The layers were separated and the organic layerwas washed with brine then concentrated under reduced pressure to givethe crude product which was triturated with DCM and filtered to give(3-amino-2,6-difluorophenyl)(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(34 g, 85 mmol, 82% yield) as a tan solid. ¹H NMR spectrum is consistentwith the structure of the compound.

Example 2:N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide(P-0021)

Synthesis ofN-[2,4-difluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(6)

To(3-amino-2,6-difluoro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(4, 2.9 g, 7.27 mmol) in pyridine (11.2 mL), was addedpyrrolidine-1-sulfonyl chloride (5, 1.68 mL, 14.53 mmol). The mixturewas stirred at room temperature for 48 hours. The resulting mixture waspoured into a saturated NH₄ Cl aqueous solution and extracted with ethylacetate. The organic layers were combined and washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated. The crudeproduct was purified by flash chromatography using an 80 g-cartridge(eluted with ethyl acetate and DCM). The desired product was obtained asa solid (6, 2.06 g, 53.3% yield). MS(ESI) [M+H+]⁺=532.8. ¹H NMR spectrumis consistent with the structure of the compound.

Synthesis ofN-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide(P-0021)

In a microwave vessel,N-[2,4-difluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(6, 0.27 g, 0.51 mmol) and (4-chlorophenyl)boronic acid (7, 0.1 g, 0.61mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(27 mg) were mixed in 1 M of potassium carbonate in water andacetonitrile (1.31 mL). The mixture was heated at 130° C. undermicrowave for 15 minutes. The resulting mixture separated into anorganic layer and aqueous layer. The aqueous layer was extracted withethyl acetate and combined with the organic layer, washed with brine,dried over sodium sulfate, filtered, and concentrated. The crude productwas purified by chromatography using a 40 g-cartridge (eluted with ethylacetate and dichloromethane). The purified product was obtained as asolid (P-0021, 0.071 g, 27% yield). MS (ESI) [M+H+]⁺=517.0 and 519.0. ¹HNMR spectrum is consistent with the structure of the compound.

The following compounds were prepared according to the protocols setforth in Examples 1, 2 and 4-9 and Schemes 1, 2 and 4-9.

TABLE 25-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine,(P- 0012),5-(4-chlorophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0013),3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0014),N-[2,4-difluoro-3-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide (P-0015),5-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P- 0018),5-(4-chlorophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0019),3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0020),N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0021),N-[3-[5-[2-(dimethylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0022),N-[2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(P- 0023)N-[2,4-difluoro-3-(5-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(P-0024),3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0025),[2-fluoro-3-(methylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (P-0026),5-(4-cyanophenyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(0027),3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine(P-0028),3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine(P-0029),5-[6-(dimethylamino)-3-pyridyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0030),5-(4-cyanophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0031),3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine(0032),3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine (0033),3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine (0034),3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine(P- 0035),3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-phenyl-1H-pyrrolo[2,3-b]pyridine(P- 0036),3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-phenyl-1H-pyrrolo[2,3-b]pyridine(P-0037),5-bromo-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P- 0038),3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0040)3-benzyloxy-N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0041)1-cyclopropyl-N-[2-fluoro-3-[5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]methanesulfonamide (P-0042)N-[2-fluoro-3-[5-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide(P-0043)N-[3-[5-(2,4-dimethoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0044)N-[2-fluoro-3-[5-(6-methyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0045)N-[3-[5-[6-(dimethylamino)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0046)N-[2-fluoro-3-[5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0047)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0048)N-[3-[5-(4-cyano-3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0049)N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0050)3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0051)5-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0052)3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0053)5-(4-cyano-3-methoxy-phenyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0054)5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0055)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0056)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0057)5-(2-cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0058)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0059)5-(4-cyano-3-methoxy-phenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0060)5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0061)N-[2-fluoro-3-[5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0062)N-[2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(P- 0063)5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0064)N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methoxy-ethanesulfonamide (P-0065) methyl3-[[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl]propanoate (P-0066)N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0067)[3-(ethylsulfamoylamino)-2-fluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (P-0068)[3-(ethylsulfamoylamino)-2-fluoro-phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P- 0069)3-[2-fluoro-3-[[isobutyl(methyl)sulfamoyl]amino]benzoyl]-5-iodo-1H-pyrrolo[2,3-b]pyridine(P- 0070)[2-fluoro-3-(isopropylsulfamoylamino)phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P- 0071)3-[2-fluoro-3-[[isobutyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0072)3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0073)N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]-2-methyl-pyrrolidine-1-sulfonamide (P-0074)3-[2-fluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0075)5-[6-(dimethylamino)-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0076)5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0077)5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0078)5-[4-(1-cyanocyclopropyl)phenyl]-3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0079)5-[4-(1-cyanocyclopropyl)phenyl]-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0080) 5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0081)5-[2-(cyclopropylamino)pyrimidin-5-yl]-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0082)3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0083)3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0084)5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0085)5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0086)5-(6-cyclopropyl-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0087)3,3-difluoro-N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]azetidine-1-sulfonamide (P-0088)4-[[(1S)-1-cyclopropylethyl]amino]-5-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-7H-pyrrolo[2,3-d]pyrimidine (P-0089)N-[3-[5-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0090)N-[3-[5-(2-cyanopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0091)N-[2-fluoro-3-[5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0092)N-[3-[5-(5-cyano-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0093)N-[3-[5-(6-cyano-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0094)N-[2-fluoro-3-[5-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0095)5-(2-cyanopyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0096)3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0097)5-(5-cyano-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0098)5-(6-cyano-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0099)5-(2-cyanopyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0100)5-(5-cyano-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0101)5-(6-cyano-3-pyridyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0102)3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0103)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0104)N-[2-fluoro-3-[5-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0105)5-[2-(dimethylamino)pyrimidin-5-yl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0106)3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0107)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0108)N-[2-fluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0109)3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-iodo-1H-pyrrolo[2,3-b]pyridine(P-0110)3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0111)3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0112)5-(6-cyclopropyl-3-pyridyl)-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0113)5-(6-cyclopropyl-3-pyridyl)-3-[2-fluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0114)3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(6-cyclopropyl-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine (P-0115)3-[2,6-difluoro-3-[[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0116)[2-fluoro-3-(propylsulfamoylamino)phenyl]-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P- 0117)[2-fluoro-3-(propylsulfamoylamino)phenyl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(P- 0223)N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0224)N-[2-fluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0225)N-[3-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-0226)N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-00227)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-0228)N-[2-fluoro-3-[5-(2-isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0229)N-[3-[5-[6-(dimethylamino)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]butane-2-sulfonamide (P-0230)N-[2-fluoro-3-[5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0231)N-[3-[5-[2-(cyclopropylamino)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0232)5-(2-cyclopropylpyrimidin-5-yl)-3-[2-fluoro-3-[[isopropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0233)N-[2-fluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0235)N-[2-fluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane-2-sulfonamide (P-0236)5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0237)5-(2-cyclopropylpyrimidin-5-yl)-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0238)5-[4-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0239)5-(2-cyclopropylpyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0240)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0241)[2-fluoro-3-(propylsulfamoylamino)phenyl]-[5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (P-0242)1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylic acid (P-0243)3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(5-ethoxypyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine (P-0244)5-[4-(1-cyano-1-methyl-ethyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0245)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3,3-dimethyl-pyrrolidine-1-sulfonamide (P-0246)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide (P-0247);N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0248)3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0249)[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[2-fluoro-3-(propylsulfamoylamino)phenyl]methanone (P-0251)3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0252)1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxamide (P-0253) methyl1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]cyclopropanecarboxylate (P-0254)5-[4-(1-cyano-1-methyl-ethyl)phenyl]-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0255)5-(2-ethoxypyrimidin-5-yl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0256) ethyl1-[[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]sulfamoyl]pyrrolidine-2-carboxylate (P-0257)4-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]morpholine (P-0258)4-[3-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]morpholine (P-0259)N-[2,4-difluoro-3-[5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0260)N-[2,4-difluoro-3-[5-(2-piperazin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0261)N-[2,4-difluoro-3-[5-[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0262)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine (P-0263) tert-butyl4-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]piperazine-1-carboxylate (P-0264)N-[2,4-difluoro-3-[5-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0265)N-[2,4-difluoro-3-[5-(2-morpholinopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0266)N-[1-[[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]sulfamoyl]pyrrolidin-3-yl]-N-methyl-acetamide (P-0267)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-piperazin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0268)N-[3-[5-[2-(azetidin-1-yl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0269)N-[2,4-difluoro-3-[5-(2-methoxythiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0270)(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide (P-0271)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-(methylamino)pyrrolidine-1-sulfonamide (P-0272)N-[2,4-difluoro-3-[5-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0273)N-[3-(5-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0274)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine (P-0275)5-[3-(1-cyanocyclopropyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0276)5-[2-(azetidin-1-yl)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0277)N-[3-[5-(2-aminopyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0279)N-[3-[5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0280)N-[2-fluoro-3-[5-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide(P-0281)N-[2,4-difluoro-3-[5-(2-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0282)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-fluoro-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (P-0283)N-[2,4-difluoro-3-[5-(2-morpholino-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0284)N-[2,4-difluoro-3-[5-[2-(4-methylpiperazin-1-yl)-4-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0285)N-[3-[5-[2-(cyclobutoxy)-4-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0286)N-[2,4-difluoro-3-[5-(2-methoxy-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0287)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3,3-difluoro-pyrrolidine-1-sulfonamide (P-0288)(3S)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0289) methyl2-[[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]sulfamoyl]propanoate (P-0291)5-[2-(dimethylamino)pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0292)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (P-0293)N-[2,4-difluoro-3-[5-[6-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0294)N-[3-[5-(2-cyclopropyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide (P-0295)5-cyclobutyl-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P- 0297)5-cyclopropyl-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P- 0298)N-[3-[5-(6-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1-sulfonamide (P-0299)5-(4-cyanophenyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0300)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0301)5-[3-(dimethylamino)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0302)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(4-pyrrolidin-1-ylphenyl)-1H-pyrrolo[2,3-b]pyridine (P-0303)2-[4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-5-methyl-1,3,4-oxadiazole (P-0304)2-[4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]-5-(methylamino)-1,3,4-thiadiazole (P-0305)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[5-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0306)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine (P-0307)5-[4-(diethylamino)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0308)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-oxoindolin-6-yl)-1H-pyrrolo[2,3-b]pyridine (P-0309)3-[5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-thienyl]-5-methyl-1,2,4-oxadiazole (P-0310)2-amino-6-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinazoline (P-0311)N-cyclopropyl-5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide (P-0312)2-(dimethylamino)-6-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]quinazoline (P-0313)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(1-hydroxycyclopropyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0314)5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]thiazole(P-0315)4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(1-hydroxy-1-methyl-ethyl)thiazole (P-0316)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-methoxypyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridine (P-0317)N-[2,4-difluoro-3-[5-(6-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0318)N-[2,4-difluoro-3-[5-[6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0319)(3S)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-methyl-pyrrolidine-1-sulfonamide (P-0320)N-[2-fluoro-3-[5-(6-morpholinopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0321)N-[2-fluoro-3-[5-[6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0322)N-[2-fluoro-3-[5-[6-(4-methylpiperazin-1-yl)-2-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0324)N-[2-fluoro-3-[5-(4-methoxypyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0325)N-[2-fluoro-3-[5-(4-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0326)(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0327)[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[2,6-difluoro-3-(methylsulfamoylamino)phenyl]methanone (P-0334)[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-[3-(ethylsulfamoylamino)-2,6-difluoro-phenyl]methanone (P-0335)5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-(sulfamoylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridine (P-0336)N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide (P-0337)(3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0338)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (P-0339)5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0340)N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide (P-0342)5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methoxy-thiazole (P-0343)3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridine (P-0344)N-[2,4-difluoro-3-[5-(2-pyrrolidin-1-ylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pyrrolidine-1-sulfonamide (P-0345)N-[3-(5-cyclobutyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]pyrrolidine-1-sulfonamide(P-0346)N-[2-fluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0347)1-allyl-N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]cyclopropanesulfonamide (P-0348)N-[2,4-difluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0349)N-[2,4-difluoro-3-[5-(5-methoxy-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]cyclopropanesulfonamide (P-0350)N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]cyclopropanesulfonamide(P-0351)The following table provides structures of certain compounds of thepresent invention and observed mass. ¹H NMR spectra were consistent withthe structures of the compounds.

MS (ESI) [M + H⁺]⁺ No. Compounds observed P-0012

428.9 P-0013

504.9 P-0014

503.0 P-0015

551.1 P-0018

410.9 P-0019

489.0 P-0020

485.1 P-0021

517.0 and 519.0 P-0022

528.1 P-0023

402.9 P-0024

532.8 P-0025

497.0 P-0026

457.0 P-0027

463.5 P-0028

439.5 P-0029

454.5 P-0030

483.5 P-0031

478.5 P-0032

454.5 P-0033

468.2 P-0034

471.5 P-0035

457.5 P-0036

453.1 P-0037

439.2 P-0040

499.0 P-0041

603.6 P-0042

454.0 P-0043

466.0 P-0044

427.5 P-0045

480.5 P-0046

509.6 P-0047

509.0 P-0048

507.0 P-0049

520.0 P-0050

530.0 P-0051

483.1 P-0052

481.0 P-0053

508.0 P-0054

494.0 P-0055

504.1 P-0056

469.0 P-0057

497.0 P-0058

495.0 P-0059

522.0 P-0060

508.0 P-0061

518.1 P-0062

483.0 P-0063

465.0 P-0064

496.0 P-0065

486.0 P-0066

514.0 P-0067

468.0 P-0068

471.0 P-0069

489.0 P-0070

499.0 P-0071

503.1 P-0072

513.5 P-0073

515.1 P-0074

511.0 P-0075

499.0 P-0076

497.1 P-0077

510.5 P-0078

527.1 P-0079

550.0 P-0080

548.0 P-0081

540.1 P-0082

524.1 P-0083

511.1 P-0084

521.1 P-0085

525.1 P-0086

509.1 P-0087

494.2 P-0088

519.5 P-0089

461.1 P-0090

490.5 P-0091

492.5 P-0092

481.5 P-0093

491.5 P-0094

491.5 P-0095

534.5 P-0096

466.5 P-0097

455.5 P-0098

465.4 P-0099

465.5 P-0100

480.5 P-0101

479.5 P-0102

479.0 P-0103

497.5 P-0104

511.6 P-0105

523.6 P-0106

484.5 P-0107

510.6 P-0108

524.6 P-0109

536.6 P-0110

489.3 P-0111

483.5 P-0112

495.5 P-0113

480.1 P-0114

508.6 P-0115

520.6 P-0116

517.5 P-0117

503.0 P-0223

391.4 P-0224

484.5 P-0225

523.6 P-0226

509.6 P-0227

517.6 P-0228

4946 P-0229

496.6 P-0230

496.6 P-0231

468.6 P-0232

522.6 P-0233

509.6 P-0235

552.5 P-0236

539.4 P-0237

522.5 P-0238

499.5 P-0239

536.6 P-0240

513.5 P-0241

525.2 P-0242

457.5 P-0243

549.6 P-0244

503.5 P-0245

506.4 P-0246

535.6 P-0247

521.5 P-0248

548.5 P-0249

507.5 P-0251

495.5 P-0252

525.5 P-0253

548.6 P-0254

563.5 P-0255

524.5 P-0256

517.2 P-0257

569.6 P-0258

558.5 P-0259

556.6 P-0260

583.6 P-0261

569.4 P-0262

584.5 P-0263

571.6 P-0264

657.7 P-0265

548.6 P-0266

570.5 P-0267

578.6 P-0268

557.5 P-0269

540.5 P-0270

520.6 P-0271

521.5 P-0272

536.6 P-0273

484.4 P-0274

429.4 P-0275

572.6 P-0276

536.5 P-0277

528.5 P-0279

500.3 P-0280

500.5 P-0281

466.5 P-0282

570.6 P-0283

490.4 P-0284

569.6 P-0285

582.5 P-0286

554.6 P-0287

514.5 P-0288

561.5 P-0289

543.4 P-0291

524.2 P-0292

516.2 P-0293

542.5 P-0294

553.5 P-0295

524.6 P-0297

431.5 P-0298

417.4 P-0299

482.5 P-0300

496.5 P-0301

539.4 P-0302

514.6 P-0303

540.5 P-0304

553.6 P-0305

584.6 P-0306

530.5 P-0307

530.2 P-0308

542.5 P-0309

526.5 P-0310

559.5 P-0311

538.5 P-0312

555.4 P-0313

566.6 P-0314

527.5 P-0315

478.5 P-0316

536.0 P-0317

503.5 P-0318

570.5 P-0319

583.6 P-0320

539.4 P-0321

552.5 P-0322

565.5 P-0324

564.8 P-0325

497.5 P-0326

481.4 P-0327

525.5 P-0334

485.4 P-0335

499.5 P-0336

471.4 P-0337

504.0 P-0338

542.9 P-0339

543.5 P-0340

567.5 P-0342

512.5 P-0343

507.5401 P-0344

511.5 P-0345

554.6 P-0346

443.5 P-0347

468.4 P-0348

443.4 P-0349

486.4 P-0350

485.5 P-0351

403.3

The following compounds are also prepared according to the protocols setforth in Examples 1, 2 and 4-9 and Schemes 1, 2 and 4-9. The data fromthe ¹H NMR and mass spectroscopies are consistent with the structures ofthe compounds.

TABLE 3 Compound Name No. (MS(ESI) [M + H⁺]⁺) Structure P-0118[2-fluoro-3- (phenylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl]methanone (519.1)

P-0119 3-[2-fluoro-3- [[methyl(phenyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridine (533.1)

P-0120 [2-fluoro-3-(3- pyridylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl]methanone (520.1)

P-0121 3-[2-fluoro-3-[[methyl(3- pyridyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridine (534.1)

P-0122 [2-fluoro-3-(thiazol-5- ylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl]methanone (526.1)

P-0123 5-[[2-fluoro-3-[5-(2-mcthoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3- carbonyl]phenyl]sulfamoyl-methyl-amino]thiazole (540.1)

P-0124 [3-(cyclopentylsulfamoylamino)-2-fluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (511.1)

P-0125 3-[3- [[cyclopentyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-methoxypyrimidin-5- yl)-1H-pyrrolo[2,3-b]pyridine(525.2)

P-0126 [3-(cyclopropylsulfamoylamino)-2-fluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (483.1)

P-0127 [2-fluoro-3-(tetrahydropyran-4- ylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl]methanone (527.1)

P-0128 3-[2-fluoro-3-[[methyl(tetrahydropyran-4-yl)sulfamoyl]amino]benzoyl]-5-(2- methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (541.2)

P-0129 3-[2-fluoro-3-[[2- fluoroethyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridine (503.1)

P-0130 3-[2-fluoro-3-[[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridine (539.1)

P-0131 3-[2-fluoro-3-[[3- fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridine (517.1)

P-0132 5-chloro-3-[2-fluoro-3-[[2- methoxyethyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (441.1)

P-0133 5-chloro-3-[2-fluoro-3-[[3- fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (443.1)

P-0134 3-[2-fluoro-3-[[3- fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-isopropylpyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridine(529.2)

P-0135 3-[2-fluoro-3-[[[1- (methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-5-(2- isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (553.2)

P-0136 5-chloro-3-[2-fluoro-3-[[[1- (methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3- b]pyridine (467.1)

P-0137 5-chloro-3-[3-[[2- cyclopropylethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridine (451.1)

P-0138 3-[3-[[2- cyclopropylethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2- isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (537.2)

P-0139 5-chloro-3-[2-fluoro-3-[[[1- (hydroxymethyl)cyclopropyl]methyl-methyl-sulfamoyl]amino]benzoyl]-1H- pyrrolo[2,3-b]pyridine (467.1)

P-0140 methyl 1-[[[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro- phenyl]sulfamoyl-methyl-amino]methyl]cyclopropanecarboxylate (495.1)

P-0141 5-chloro-3-[3-[[2- cyanoethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (436.1)

P-0142 (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)- [2-fluoro-3-(3-methoxypropylsulfamoylamino)phenyl] methanone (441.1)

P-0143 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-4-methyl- piperazine-1-sulfonamide (452.1)

P-0144 5-chloro-3-[2-fluoro-3-[[(2-hydroxy-2- methyl-propyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3- b]pyridine (455.1)

P-0145 5-chloro-3-[2-fluoro-3-[[(2-hydroxy-1,1- dimethyl-ethyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3- b]pyridine (455.1)

P-0146 N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]azetidine-1-sulfonamide (493.1)

P-0147 N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]-3-fluoro-azetidine-1- sulfonamide (511.1)

P-0148 5-(2-cyclopropylpyrimidin-5-yl)-3-[2- fluoro-3-[[methyl(oxetan-3-yl)sulfamoyl]amino]benzoyl]-1H- pyrrolo[2,3-b]pyridine (523.1)

P-0149 3-[3- [[cyclobutyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (521.2)

P-0150 5-chloro-3-[2-fluoro-3- [[methyl(tetrahydrofuran-3-yl)sulfamoyl]amino]benzoyl]-1H- pyrrolo[2,3-b]pyridine (453.1)

P-0151 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-methoxy- pyrrolidine-1-sulfonamide(453.1)

P-0152 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3- (methylamino)pyrrolidine-1-sulfonamide(452.1)

P-0153 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3- (dimethylamino)pyrrolidine-1-sulfonamide(466.1)

P-0154 N-[3-[5-[6-(1-cyanocyclopropyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-phenyl]pyrrolidine-1- sulfonamide (531.2)

P-0155 1-[5-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxamide (549.2)

P-0156 1-[5-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxylic acid (550.2)

P-0157 1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]phenyl]cyclopropanecarboxamide (548.2)

P-0158 1-[4-[3-[2-fluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]phenyl]cyclopropanecarboxylic acid (548.2)

P-0159 3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(5-methoxypyrazin-2-yl)-1H- pyrrolo[2,3-b]pyridine (471.1)

P-0160 5-[5-(dimethylamino)pyrazin-2-yl]-3-[3-(dimethylsulfamoylainino)-2-fluoro- benzoyl]-1H-pyrrolo[2,3-b]pyridine(484.2)

P-0161 3-[3-(dimethylsulfamoylamino)-2-fluoro-benzoyl]-5-(6-methoxypyridazin-3-yl)-1H- pyrrolo[2,3-b]pyridine (471.1)

P-0162 4-[5-[3-[3- [[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5- yl]pyrimidin-2-yl]morpholine(540.2)

P-0163 5-chloro-3-[2-fluoro-3-[[(4-fluorophenyl)-methyl-sulfamoyl]amino]benzoyl]-1H- pyrrolo[2,3-b]pyridine (477.1)

P-0164 3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(1-methylpyrrol-3-yl)- 1H-pyrrolo[2,3-b]pyridine(442.1)

P-0165 3-[2-fluoro-3- [[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine (471.2)

P-0166 5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin- 5-yl]thiazole (460.1)

P-0167 3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-5-(1-methylimidazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine(457.1)

P-0168 4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin- 5-yl]oxazole (444.1)

P-0169 [2,6-difluoro-3- (phenylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl]methanone (537.1)

P-0170 3-[2,6-difluoro-3- [[methyl(phenyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridine (551.1)

P-0171 [2,6-difluoro-3-(3- pyridylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl]methanone (538.1)

P-0172 3-[2,6-difluoro-3-[[methyl(3-pyridyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridine (552.1)

P-0173 [2,6-difluoro-3-(thiazol-5- ylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridin-3-yl]methanone (544.1)

P-0174 5-[[2,4-difluoro-3-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3- carbonyl]phenyl]sulfamoyl-methyl-amino]thiazole (558.1)

P-0175 [3-(cyclopentylsulfamoylamino)-2,6-difluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl]methanone (529.1)

P-0176 3-[3- [[cyclopentyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2- methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (543.2)

P-0177 [3-(cyclopropylsulfamoylamino)-2,6-difluoro-phenyl]-[5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl]methanone (501.1)

P-0178 [2,6-difluoro-3-(tetrahydropyran-4-ylsulfamoylamino)phenyl]-[5-(2- methoxypyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone (545.1)

P-0179 3-[2,6-difluoro-3-[[methyl(tetrahydropyran-4-yl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridine (559.1)

P-0180 3-[2,6-difluoro-3-[[2- fluoroethyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H- pyrrolo[2,3-b]pyridine (521.1)

P-0181 3-[2,6-difluoro-3-[[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridine (556.1)

P-0182 3-[2,6-difluoro-3-[[3- fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-methoxypyrimidin-5-yl)- 1H-pyrrolo[2,3-b]pyridine (534.1)

P-0183 5-chloro-3-[2,6-difluoro-3-[[2-methoxyethyl(methyl)sulfamoyl]amino] benzoyl]-1H-pyrrolo[2,3-b]pyridine(458.1)

P-0184 5-chloro-3-[2,6-difluoro-3-[[3-fluoropropyl(methyl)sulfamoyl]amino] benzoyl]-1H-pyrrolo[2,3-b]pyridine(561.1)

P-0185 3-[2,6-difluoro-3-[[3- fluoropropyl(methyl)sulfamoyl]amino]benzoyl]-5-(2-isopropylpyrimidin-5-yl)- 1H-pyrrolo[2,3-b]pyridine(547.2)

P-0186 3-[2,6-difluoro-3-[[[1- (methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-5-(2- isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (571.2)

P-0187 5-chloro-3-[2,6-difluoro-3-[[[1-(methoxymethyl)cyclopropyl]-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3- b]pyridine (485.1)

P-0188 5-chloro-3-[3-[[2- cyclopropylethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridine (469.1)

P-0189 3-[3-[[2- cyclopropylethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2- isopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (555.2)

P-0190 5-chloro-3-[2,6-difluoro-3-[[[1-(hydroxymethyl)cyclopropyl]methyl- methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (485.1)

P-0191 methyl 1-[[[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro- phenyl]sulfamoyl-methyl-amino]methyl]cyclopropanecarboxylate (513.1)

P-0192 5-chloro-3-[3-[[2- cyanoethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridine (454.0)

P-0193 (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)- [2,6-difluoro-3-(3-methoxypropylsulfamoylamino)phenyl] methanone (459.1)

P-0194 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-methyl- piperazine-1-sulfonamide(470.1)

P-0195 5-chloro-3-[2,6-difluoro-3-[[(2-hydroxy-2- methyl-propyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3- b]pyridine (473.1)

P-0196 5-chloro-3-[2,6-difluoro-3-[[(2-hydroxy-1,1-dimethyl-ethyl)-methyl- sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (473.1)

P-0197 N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]azetidine-1-sulfonamide (511.1)

P-0198 N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]-3-fluoro-azetidine-1- sulfonamide (529.1)

P-0199 5-(2-cyclopropylpyrimidin-5-yl)-3-[2,6-difluoro-3-[[methyl(oxetan-3- yl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3-b]pyridine (541.1)

P-0200 3-[3- [[cyclobutyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (539.2)

P-0201 5-chloro-3-[2,6-difluoro-3- [[methyl(tetrahydrofuran-3-yl)sulfamoyl]amino]benzoyl]-1H- pyrrolo[2,3-b]pyridine (471.1)

P-0202 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3- methoxy-pyrrolidine-1-sulfonamide(471.1)

P-0203 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-(methylamino)pyrrolidine-1-sulfonamide (470.1)

P-0204 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-(dimethylamino)pyrrolidine-1-sulfonamide (484.1)

P-0205 N-[3-[5-[6-(1-cyanocyclopropyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine- 1-sulfonamide (549.1)

P-0206 1-[5-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxamide (567.2)

P-0207 1-[5-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]-2-pyridyl]cyclopropanecarboxylic acid (568.1)

P-0208 1-[4-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]phenyl]cyclopropanecarboxamide (566.2)

P-0209 1-[4-[3-[2,6-difluoro-3-(pyrrolidin-1-ylsulfonylamino)benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]phenyl]cyclopropanecarboxylic acid (567.1)

P-0210 3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(5-methoxypyrazin-2- yl)-1H-pyrrolo[2,3-b]pyridine(489.1)

P-0211 5-[5-(dimethylamino)pyrazin-2-yl]-3-[3-(dimethylsulfamoylainino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine (502.1)

P-0212 3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(6-methoxypyridazin- 3-yl)-1H-pyrrolo[2,3-b]pyridine(489.1)

P-0213 4-[5-[3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyrimidin-2-yl]morpholine (558.2)

P-0214 5-chloro-3-[2,6-difluoro-3-[[(4- fluorophenyl)-methyl-sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3- b]pyridine (495.0)

P-0215 3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(1-methylpyrrol-3-yl)- 1H-pyrrolo[2,3-b]pyridine(460.1)

P-0216 3-[2,6-difluoro-3- [[methyl(propyl)sulfamoyl]amino]benzoyl]-5-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine (489.1)

P-0217 5-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]thiazole (478.1)

P-0218 3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(1-methylimidazol-4- yl)-1H-pyrrolo[2,3-b]pyridine(475.1)

P-0219 4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]oxazole (462.1)

P-0220 6-[3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]quinoline (508.1)

P-0221 6-[3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]quinazoline (509.1)

P-0222 6-[3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3- b]pyridin-5-yl]-1,3-benzothiazole(514.1)

Example 3: Preparation of5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0017)

Synthesis of 1-[(ethyl(methyl)sulfamoyl)amino]-2,4-difluoro-benzene (10)

To a solution of 2,4-Difluoroaniline (2.21 g, 17.13 mmol) indichloroethane (10 mL) were added 4-Dimethylaminopyridine (0.1 g, 0.82mmol), N-ethyl-N-methyl-sulfamoyl chloride (2.7 g, 17.13 mmol) andpyridine (2 g, 25.28 mmol). The mixture was stirred at room temperatureovernight. The resulting mixture was poured into an aqueous potassiumcarbonate solution, and extracted with ethyl acetate (EtOAc). Theorganic layer was washed with brine, dried over sodium sulfate andfiltered. The filtrate was concentrated and purified by silica gelcolumn chromatography using 20% to 100% ethyl acetate in hexane as aneluent to give th desired product (10, 3.08 g, 71.8% yield). MS (ESI)[M+H+]⁺=250.8. ¹H NMR spectrum is consistent with the structure of thecompound.

Synthesis of1-[(ethyl(methyl)sulfamoyl)amino]-2,4-difluoro-3-formyl-benzene (11)

To a mixture of 1-[(ethyl(methyl)sulfamoyl)amino]-2,4-difluoro-benzene(10, 3.08 g, 12.31 mmol) in tetrahydrofuran (THF) (25.0 mL) under anatmosphere of nitrogen at −78° C. was added 2.5M n-butyllithium (n-BuLi)in THF (5 mL). The colorless reaction mixture was kept at −78° C. forone hour and 2.5M n-BuLi in THF (5.4 ml) was added to the reactionmixture. The reaction was kept at −78° C. for 1 hr and addedN,N-Dimethylformamide (DMF) (1.8 mL, 23.25 mmol). The reaction mixtureturned into solid. The solid reaction mixture was shaken for about 5minutes to obtain a slurry. The reaction mixture was kept in a dryice-acetone bath for 1 hr and was allowed to warm up to room temperaturefor 1 hour. The reaction mixture was poured into an aqueous ammoniachloride solution and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, concentrated andpurified with silica gel column chromatography using 30% to 100% ethylacetate in hexane as an eluent to give the desired product (11, 1.10 g,32.1% yield). MS (ESI) [M+H+]⁺=278.8. ¹H NMR spectrum is consistent withthe structure of the compound.

Synthesis of 1-(benzenesulfonyl)-5-bromo-3-iodo-pyrrolo[2,3-b]pyridine(12)

To a solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (2.7 g, 8.36mmol) in DMF (30.0 mL) was added sodium hydride (60%, 0.37 g, 9.2 mmol)at room temperature. After 10 minutes, benzenesulfonyl chloride (1.13ml, 8.78 mmol) was added to and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was poured in to water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated, filtered andwashed with ethyl acetate to obtain the desired product 12 as a whitesolid (2.70 g). The mother liquid was purified with silica gel columnchromatography using 20% to 100% ethyl acetate in hexane as an eluent togive addition product (0.90 g). The combined yield is 93.0%. MS (ESI)[M+H+]⁺=464.1. ¹H NMR spectrum is consistent with the structure of thecompound.

Synthesis of1-(benzenesulfonyl)-5-bromo-3-[[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-phenyl]-hydroxy-methyl]pyrrolo[2,3-b]pyridine(13)

Step 1: To a solution of1-[[ethyl(methyl)sulfamoyl]amino]-2,4-difluoro-3-formyl-benzene (11,0.76 g, 2.73 mmol) in THF (5 mL), under nitrogen at −78° C., was added1M mesitylmagnesium bromide in THF (2.8 ml). The reaction solution wasstirred for 40 minutes.

Step 2: To 1-(benzenesulfonyl)-5-bromo-3-iodo-pyrrolo[2,3-b]pyridine(17, 1.76 g, 3.79 mmol) in THF (10 mL), under an atmosphere of nitrogenat −40° C., was added a solution of i-PrMgCl (2.0 M in THF, 1.9 mL). Thereaction mixture was allowed to warm up to 5° C. in 1 hour. The reactionmixture was cooled to −40° C. and added the reaction solution fromstep 1. The resulting reaction mixture was allowed to warm to roomtemperature in 1 hr, poured into water and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,concentrated and purified by silica gel column chromatography using 20%to 100% ethyl acetate in hexane as an eluent to give the desired product(13, 1.10 g, 65.4%). MS (ESI) [M+H⁺]⁺=614.7 and 616.7. ¹H NMR spectrumis consistent with the structure of the compound.

Synthesis of1-(benzenesulfonyl)-5-cyano-3-[[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-phenyl]-hydroxy-methyl]pyrrolo[2,3-b]pyridine(14)

To1-(benzenesulfonyl)-5-bromo-3-[[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-phenyl]-hydroxy-methyl]pyrrolo[2,3-b]pyridine(13, 500 mg, 0.81 mmol) were added zinc cyanide (0.05 ml, 0.77 mmol),zinc, tris(dibenzylideneacetone)dipalladium(0) (90 mg, 0.09 mmol),1,1′-Bis(diphenylphosphino)ferrocene (90 mg, 0.16 mmol), and DMF (10 ml)under nitrogen. The reaction mixture was heated to 120° C. overnight.The resulting reaction mixture was poured into an aqueous potassiumcarbonate solution and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate and filtered. Thefiltrate was concentrated and purified with silica gel columnchromatography using 20% to 100% ethyl acetate in hexane as an eluent togive the desired product (14, 0.20 g, 43.8% yield). MS (ESI)[M+H⁺]⁺=562.0. ¹H NMR spectrum is consistent with the structure of thecompound.

Synthesis of1-(benzenesulfonyl)-5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine(15)

To1-(benzenesulfonyl)-5-cyano-3-[[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-phenyl]-hydroxy-methyl]pyrrolo[2,3-b]pyridine(14, 0.2 g, 0.36 mmol) in methylene chloride (10 mL) was addedDess-Martin Periodinane (0.18 g, 0.43 mmol). The reaction mixture wasstirred at room temperature for 20 minutes. The reaction mixture wasconcentrated, and purified by silica gel column chromatography using 25%to 100% ethyl acetate in hexane as an eluent to give th desired product(15, 170 mg, 85.3% yield). MS (ESI) [M+H⁺]⁺=560.5. ¹H NMR spectrum isconsistent with the structure of the compound.

Synthesis of5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine(P-0017)

To1-(benzenesulfonyl)-5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine(15, 0.17 g, 0.3 mmol) in THF (10 mL) was added tetra-n-butylamoniumfluoride (TBAF) (0.19 g, 0.61 mmol). The reaction mixture was stirred atroom temperature overnight. The resulting reaction mixture was pouredinto an aqueous ammonia chloride solution and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography using 2% to 10% methanol in methylenechloride as an eluent to give the product (P-0017, 74.5 mg, 58.5%yield). MS (ESI) [M+H⁺]⁺=420.1. ¹H NMR spectrum is consistent with thestructure of the compound.

The following compounds were prepared according to the protocols setforth in Example 3 and Scheme 3.

-   5-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0012),-   N-[2,4-difluoro-3-(5-fluoro-4-iodo-H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide    (P-0013),-   5-chloro-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0018),-   N-[2-fluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide    (P-0023),-   5-bromo-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0038),-   5-cyano-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine    (P-0039).    The following table provides structures of certain compounds of the    present invention and observed mass. ¹H NMR spectra were consistent    with the structures of the compounds.

MS(ESI) [M + H⁺]⁺ Compounds observed P-0012

428.9 P-0015

551.1 P-0018

410.9 P-0023

402.9 P-0038

455.0 P-0039

454.9 and 456.9

Example 4: Preparation ofN-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide(P-0016)

Step 1—Synthesis of 2,6-difluoro-3-nitrobenzoyl chloride (2)

In a round flask, 2,6-difluoro-3-nitrobenzoic acid (5.5 g, 0.03 mol) wasadded Thionyl chloride (20 mL, 0.27 mol) and N,N-Dimethylformamide (100μl, 0.001 mol). The reaction mixture was placed in an oil bath at 80° C.for 4 hrs. All volatiles were removed and the residue was stripped fromtoluene twice and dried in high vacuo to give a yellow oily liquid (2,5.95 g, 99%). It will be used as is.

Step 2—Synthesis of(2,6-difluoro-3-nitro-phenyl)-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(18)

In a Vial, 5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (450 mg, 1.72 mmol)was cooled in an ice-water bath and added Trifluoromethanesulfonic acid(1.52 ml, 17.17 mmol). The reaction was stirred in an ice-water bath for5 minutes and followed by adding 2,6-difluoro-3-nitrobenzoyl chloride(2, 500 mg, 2.26 mmol). The resulting reaction mixture was stirred at anice-water bath for 20 min and warmed up to room temperature. After 24hrs at room temperature, the reaction mixture was quenched with 5 mL ofmethanol and stirred at r.t. for 1 hr. The mixture was poured to thesaturated NaHCO₃ aqueous solution and extracted with EtOAc. The organiclayer was washed with water and brine, dried with MgSO₄. The volatileswere removed under vacuo. The residue was suspended in acetonitrile andsonicated for 45 mins. The precipitate material was collected byfiltration and washed with acetonitrile. The desired product (18, 532mg, 69%) was a tan solid. MS (ESI) [M+H⁺]⁺=447.8.

Step 3—Preparation of(3-amino-2,6-difluoro-phenyl)-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(19)

In a round flask,(2,6-difluoro-3-nitro-phenyl)-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(0.53 g, 0.001 mol) was added EtOH (50 ml) and TIN(II) CHLORIDE (788 mg,4.16 mmol). The reaction mixture was heated at 50° C. for over weekend.The reaction mixture treated with 50 mL of water and 50 mL saturatedsodium bicarbonate. Additional ethyl acetate (20 mL) was added and themilky suspension was treated with celite and mixed well beforefiltering. The filtrate was added by brine to give clear layers thatwere separated. The organic layer was washed with water and brine anddried with MgSO4. The volatiles were removed under vacuum. The desiredproduct was isolated by silica gel column chromatography (EtOAc/Hexane,0-80% gradient) as an off-white solid (19, 365 mg, 73%). MS (ESI)[M+H⁺]⁺=417.9.

Step 4—Preparation ofN-[2,4-difluoro-3-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(P-0015)

In a round flask,(3-amino-2,6-difluoro-phenyl)-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(19, 180 mg, 0.43 mmol) was dissolved in 4 mL of THF and added PYRIDINE(106 μl, 1.29 mmol) and pyrrolidine-1-sulfonyl chloride (110 mg, 0.65mmol). The solution was stirred at room temperature for about 90 hrs.The reaction mixture was added water and extracted with ethyl acetate.The organic layer was washed with water and brine and dried by MgSO4.The volatiles were removed under vacuum. The desired product wasisolated by silica gel column chromatography (EtOAc/Hexane, 0-80%gradient) as a light yellow solid (P-0015, 99 mg, 41%). MS (ESI)[M+H⁺]⁺=551.1.

Step 5—Preparation ofN-[3-[4-(cyclopropylmethylamino)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]pyrrolidine-1-sulfonamide(P-0016)

ToN-[2,4-difluoro-3-(5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]pyrrolidine-1-sulfonamide(95 mg, 0.17 mmol) in isopropyl alcohol (2 ml) was addedcyclopropylmethanamine (0.5 mL, 49.11 mg, 0.69 mmol). The resultingsolution was stirred at 90° C. overnight. The reaction mixture wasconcentrated in vacuo and purified by silica gel on the companion with 8g-cartridge using EtOAc/Hexane (0-65% gradient) as an eluent. Theresulting product was further purified by prep HPLC. The pure fractionswere combined and were dried on a lyophilizer. The desired product wasobtained as a tan solid (P-0016, 6.5 mg, 7.6% yield). MS (ESI)[M+H⁺]⁺=494.4. H¹ NMR(THF-d₈) spectrum is consistent with the structureof the compound.

Example 5: Synthesis ofN-(2-Chloro-5-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridin-3-yl)-benzenesulfonamide25

N-(2-Chloro-5-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyridin-3-yl)-benzenesulfonamide7 was prepared in six steps from 5-Bromo-1H-pyrrolo[2,3-b]pyridine 1 asshown in Scheme 1.

Step 1—Preparation of2,6-Difluoro-3-nitro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(21)

To 5-Bromo-1H-pyrrolo[2,3-b]pyridine (20, 0.5 g, 2 mmol) in nitromethane(11 mL) was added aluminum trichloride (1.64 g, 12 mmol). The mixturebecame clear instantly. The resulting solution was stirred at roomtemperature for 1 hour. To this mixture was then added2,6-difluoro-3-nitro-benzoyl chloride (0.681 g, 3 mmol) in nitromethane.The reaction mixture was stirred at 45° C. overnight. The reaction wasquenched with methanol. After a few minutes, some solids were crashedout. Solids were collected by filtration, and it was clean product (21,0.58 g). Additional product was obtained from filtrate throughchromatography (eluted with ethyl acetate and dichloromethane).

Preparation of 2,6-Difluoro-3-nitro-benzoyl chloride: To2,6-Difluoro-3-nitro-benzoic acid (2 g, 1 mmol) was added thionylchloride (0.9 mL, 12 mmol). The reaction mixture was stirred at 57° C.overnight. After removal of solvent, the residue was stripped once fromtoluene. This gave brown oil was checked by NMR which indicated completeconversion to the acid chloride (18 g, 99%). This material was used asis, without purification.

Step 2—Preparation of(3-Amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(22)

To a suspension of2,6-difluoro-3-nitro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(0.123 g, 0.287 mmol) in ethyl acetate (5 mL) and tetrahydrofuran (5 mL)was added stannous chloride, dihydrate (0.223 g, 1 mmol). The reactionmixture was stirred at 60° C. for 24 hours. The reaction mixture waspoured into a mixture of 25 mL of water and 25 mL of saturated sodiumbicarbonate. This milky mixture was filtered through a bed of Celite,and the Celite bed was washed with some ethyl acetate. The two layers ofthe filtrate were separated. The organic layer were collected, washedwith brine, and dried over anhydrous sodium sulfate. After removal ofdrying agent and solvent, the residue was purified by chromatography(eluted with ethyl acetate and dichloromethane) to provide solid product(22, 0.1 g, 87%).

Step 3—Preparation of isobutane-1-sulfonic acid[3-(5-bromo-H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide(23)

A mixture of(3-Amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(47 mg, 0.13 mmol), isobutane-1-sulfonylchloride (62 mg, 0.4 mmol), andpyridine (0.5 mL, 6 mmol), in tetrahydrofuran (3 mL) was irradiated inmicrowave at 130° C. for 10 minutes. The mixture was diluted by ethylacetate and then washed with water, brine, and dried over anhydroussodium sulfate. After removal of drying agent and solvent, the residuewas purified by chromatography (eluted with hexanes and ethyl acetate)to provide desired product (23, 24 mg, 36%).

Step 4—Preparation of isobutane-1-sulfonic acid{2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide(24)

To a suspension of compound 23, an appropriate amount ofbis(pinacolato)diboron, and potassium acetate in anhydrous 1,4-dioxaneor an appropriate solvent is added[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (complexwith dichloromethane 1:1). The suspension is heated in an oil bath for 2to 24 hours. After cooling to room temperature, the mixture is dilutedwith ethyl acetate, filtered through a Celite pad, and concentrated. Theresidue is purification by chromatography to provideisobutane-1-sulfonic acid{2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide(24).

Step 5—Preparation of isobutane-1-sulfonic acid{3-[5-phenyl-H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(25)

To a mixture of compound 24, phenyl bromide and an appropriate amount ofcesium carbonate in anhydrous 1,4-dioxane or an appropriate solvent isadded an appropriate amount of tetrakis(triphenylphosphine)palladium.The mixture is then heated in an oil bath for 2 to 48 hours. Aftercooling to room temperature, the mixture is diluted with ethyl acetateor an appropriate solvent, filtered through Celite, and concentrated.The residue is purified by chromatography to provideisobutane-1-sulfonic acid{3-[5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(25).

Example 6: Preparation of Compound 30

Compound 30 is prepared in four steps from5-Bromo-1H-pyrrolo[2,3-b]pyridine 1 as shown in Scheme 2.

Step 1—Preparation of Compound 27

To 5-Bromo-1H-pyrrolo[2,3-b]pyridine (20) in nitromethane or anappropriate solvent is added an appropriate amount of aluminumtrichloride. The resulting solution is stirred at room temperature for 1to 24 hour (heated in an oil bath if necessary). To this mixture is thenadded appropriate amount of benzoyl chloride in nitromethane or anappropriate solvent. The reaction mixture is heated in an oil bath for 2to 48 hours. The reaction is quenched with methanol or an appropriatesolvent. Precipitate is collected by filtration, and it is purified bychromatography to provide compound 27.

Step 2—Preparation of Compound 28

To a suspension of compound 20 in an appropriate solvent is added anappropriate amount of stannous chloride. The reaction mixture is heatedin an oil bath for 2 to 48 hours. The reaction mixture is poured into amixture of water and saturated sodium bicarbonate. This milky mixturewas filtered through a bed of Celite, and the Celite bed was washed withan appropriate solvent. The organic layers were collected, washed withbrine, and dried over anhydrous sodium sulfate. After removal of dryingagent and solvent, the residue is purified by chromatography to providecompound 28.

Step 3—Preparation of Compound 29

A mixture of compound 28, an appropriate sulfonyl chloride, and anappropriate amount of pyridine in an appropriate solvent is irradiatedin microwave at over 50° C. for 10 to 60 minutes. The mixture is dilutedby an appropriate solvent and then washed with water, brine, and driedover anhydrous sodium sulfate. After removal of drying agent andsolvent, the residue is purified by chromatography to provide compound29.

Step 4—Preparation of Compound 30

To a mixture of compound 29, an appropriate boronic acid or a boronicester, and an appropriate amount of cesium carbonate in anhydrous1,4-dioxane or an appropriate solvent is added an appropriate amount oftetrakis(triphenylphosphine)palladium. The mixture is then heated in anoil bath for 2 to 48 hours. After cooling to room temperature, themixture is diluted with ethyl acetate or an appropriate solvent,filtered through Celite, and concentrated. The residue is purificationby chromatography to provide compound 30. When boronic acid or a boronicester is not commercially available, boronic acid or ester of compound29 is prepared by following the procedure described at Example 1, step4.

Compound 30 is then prepared by following the abovementioned procedurefrom boronic acid or ester of compound 29 and an appropriate halide.

Example 7: Preparation of Compound 30

Compound 30 can also be prepared in three steps from5-Bromo-1H-pyrrolo[2,3-b]pyridine 11 as shown in Scheme 3.

Step 1—Preparation of compound 31

To a mixture of compound 27, an appropriate boronic acid or a boronicester, and an appropriate amount of cesium carbonate in anhydrous1,4-dioxane or an appropriate solvent is added an appropriate amount oftetrakis(triphenylphosphine)palladium. The mixture is then heated in anoil bath for 2 to 48 hours. After cooling to room temperature, themixture is diluted with ethyl acetate or an appropriate solvent,filtered through Celite, and concentrated. The residue is purificationby chromatography to provide compound 31. When boronic acid or a boronicester is not commercially available, boronic acid or ester of compound27 is prepared by following the procedure described at Example 1, step4. Compound 31 is then prepared by following the abovementionedprocedure from boronic acid or ester of compound 27 and an appropriatehalide.

Step 2—Preparation of compound 32

To a suspension of compound 31 in an appropriate solvent is added anappropriate amount of stannous chloride. The reaction mixture is heatedin an oil bath for 2 to 48 hours. The reaction mixture is poured into amixture of water and saturated sodium bicarbonate. This milky mixturewas filtered through a bed of celite, and the celite bed was washed withan appropriate solvent. The organic layers were collected, washed withbrine, and dried over anhydrous sodium sulfate. After removal of dryingagent and solvent, the residue is purified by chromatography to providecompound 32.

Step 3—Preparation of compound 30

A mixture of compound 32, an appropriate sulfonyl chloride, and anappropriate amount of pyridine in an appropriate solvent is irradiatedin microwave at over 50° C. for 10 to 60 minutes. The mixture is dilutedby an appropriate solvent and then washed with water, brine, and driedover anhydrous sodium sulfate. After removal of drying agent andsolvent, the residue is purified by chromatography to provide compound30.

Example 8: Preparation of Compound 34

Compound 34 is prepared in two steps from5-Bromo-1H-pyrrolo[2,3-b]pyridine 1 as shown in Scheme 8.

Step 1—Preparation of compound 33

To 5-Bromo-1H-pyrrolo[2,3-b]pyridine (20) in nitromethane or anappropriate solvent is added appropriate amount of aluminum trichloride.The resulting solution is stirred at room temperature for 1 to 48 hour(heated in an oil bath if necessary). To this mixture is then addedappropriate amount of benzoyl chloride in nitromethane or an appropriatesolvent. The reaction mixture is heated in an oil bath for 2 to 48hours. The reaction is quenched with an appropriate solvent. Precipitateis collected by filtration, and it is purified by chromatography toprovide compound 33.

Step 2—Preparation of compound 34

To a mixture of compound 33, an appropriate boronic acid or a boronicester, and an appropriate amount of cesium carbonate in anhydrous1,4-dioxane or an appropriate solvent is added an appropriate amount oftetrakis(triphenylphosphine)palladium. The mixture is then heated in anoil bath for 2 to 48 hours. After cooling to room temperature, themixture is diluted with ethyl acetate or an appropriate solvent,filtered through Celite, and concentrated. The residue is purificationby chromatography to provide compound 34.

When boronic acid or a boronic ester is not commercially available,boronic acid or ester of compound 33 is prepared by following theprocedure described at Example 6, step 4. Compound 34 is then preparedby following the abovementioned procedure from boronic acid or ester ofcompound 33 and an appropriate halide.

Example 9: Prepartion of3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(5-ethoxypyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine(37)

Step 1

Into a microwave vial5-bromo-3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine35 (70% pure, 200 mg, 0.3 mmol) was placed with4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(216.75 mg, 0.85 mmol) and potassium acetate (100 mg, 1.02 mmol) wasadded followed by 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (50 mg, 0.06 mmol). 1,4-dioxane (3mL) was added and the mixture was irradiated in microwave reactor at145° C. for 45 minutes. The formation of the intermediate 36 wasconfirmed by LCMS. MS ESI [M+H+]+=506.95 [M−H+]−=504.85.

Step 2

2-Bromo-5-ethoxypyrazine (200 mg, 0.99 mmol) in 1.5 mL of 1,4-dioxanewas added into the reaction mixture, made in step 1, followed by theaddition of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (50 mg, 0.06 mmol) and 1M potassium carbonate inwater (1.3 ml). The reaction was irradiated in microwave reactor at 135°C. for 10 minutes. After cooling the reaction was placed into brine and1N HCl; the aqueous were extracted with ethyl acetate. The organiclayers were combined and dried over anhydrous sodium sulfate. Afterremoval of drying agent and solvent, the residue was purified by silicagel chromatography eluting with a gradient of ethyl acetate: hexanes(10-100%) to provide3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]-5-(5-ethoxypyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine37 (16 mg, 10.2%). ESI [M+H+]+=503.0 [M−H+]−=501.1.

Example 10: Compound Properties

While the inhibitory activity of the compounds on any Rafkinase isimportant to their activity in treating of disease, the compoundsdescribed herein show favorable properties that provide advantages as apharmaceutical as well.

Assays for biochemical and cell based activity are known in the art, forexample, as described in PCT publication WO 2007/002433, the disclosureof which is hereby incorporated by reference as it relates to suchassays. For example, the biochemical activity IC₅₀ values are determinedwith respect to inhibition of B-Raf V600E kinase activity or p-Erkkinase activity, where inhibition of phosphorylation of a peptidesubstrate is measured as a function of compound concentration. Compoundsto be tested are diluted in dimethyl sulfoxide to a concentration of 0.1mM. These are serially diluted 15 μL into 30 μL of dimethyl sulfoxideseven times in 96 well plates for a total of 8 dilution points, and foreach dilution point 1 μL is added to a well of an assay plate. Platesare prepared such that each well in a 384 well plate contains 1 μL ofcompound in 10 μL volume with 0.1 ng Raf enzyme (i.e. any of B-Raf,c-Raf-1 or B-Raf V600E, Upstate Biotechnology or preparead by methodsknown to one of skill in the art), 50 mM HEPES, pH 7.0, 50 mM NaCl, 2 mMMgCl₂, 1 mM MnCl₂, 0.01% Tween-20, 1 mM DTT, and 100 nM biotin-MEK1 assubstrate. The reaction is started with addition of 10 μL of 200 μM ATP(i.e. final 100 μM ATP). After incubation of the kinase reaction for 45minutes at room temperature, 5 μL/well of Stop Solution is added (25 mMHepes pH 7.5, 100 mM EDTA, 0.01% BSA with donor beads (Streptavidincoated beads, Perkin Elmer), acceptor beads (Protein A coated, PerkinElmer), and anti phosphor MEK1/2 antibody (CellSignal), each at finalconcentration 10 μg/mL). The plates are incubated for 3 hours at roomtemperature and read on Envision reader (Perkin Elmer). Phosphorylationof Mek1 results in binding of the anti-phosphor-MEK1/2antibody andassociation of the donor and acceptor beads such that signal correlateswith kinase activity. The signal vs. compound concentration is used todetermine the IC₅₀.

Compounds are assessed in a variety of cell based assays. For examplehuman cell lines with B-RafV600E mutation (A375 melanoma, SKMEL3melanoma, and COLO205 colon adenocarcinoma), as well as tumorigenic celllines with wild-type B-RAF (SW620 colon adenocarcinoma) or with Rasmutations (SKMEL2 melanoma and IPC298 melanoma). Similar assays may beused to assess additional tumorigenic cell lines with Ras mutations,including, but not limited to, M202, M207, M243, M244, M296, S117,HCT116, HCT15, DLD1, MiaPaCa, A549, NCI-H23, NCI-H460, HOP62, MDA-MB231,Hs-578T, HL60, MOLT-4, and CCRF-CEM.

On day 1, cells are counted, then centrifuged in a conical tube for 5minutes at 1000 rpm. The supernatant is removed and cells arere-suspended as follows:

-   -   SW620 (ATCC catalog # CCL-27): resuspend in Leibovitz's L-15        medium, 2 mM L-glutamine, 10% fetal bovine serum to 6×10⁴        cells/mL.    -   A375 (ATCC catalog # CRL-1619): resuspend in Dulbecco's modified        Eagle's medium, 4 mM L-glutamine, 4.5 g/L D-glucose, 10% fetal        bovine serum to 6×10⁴ cells/mL.    -   COLO205 (ATCC catalog # CCL-222): resuspend in RPMI 1640, 2 mM        L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L D-glucose, 10        mM HEPES, 1.0 mM sodium pyruvate, 10% fetal bovine serum to        6×10⁴ cells/mL.    -   SKMEL2 (ATCC catalog # HTB-68): resuspend in Minimum Eagle        essential medium, 2 mM L-glutamine, 1.5 g/L sodium bicarbonate,        0.1 mM non-essential amino acids, 1.0 mM sodium pyruvate, 10%        fetal bovine serum to 6×10⁴ cells/mL.    -   SKMEL3 (ATCC catalog # HTB-69): resuspend in McCoy's 5A medium,        1.5 mM L-glutamine, 15% fetal bovine serum to 6×10⁴ cells/mL.    -   IPC298 (DSMZ catalog # ACC 251): resuspend in RPMI 1640, 2 mM        L-glutamine, 10% fetal bovine serum to 6×10⁴ cells/mL.

The cells are plated, 50 μL in each well of a 96-well dish (Coming 3610)and incubated at 37° C. in 5% CO₂ overnight, cells plated to a finalconcentration of cells as follows:

-   -   SW620: 5,000 cells per well.    -   A375: 2,000 cells per well.    -   COLO205: 2,000 cells per well.    -   SKMEL2: 2,000 cells per well.    -   SKMEL3: 3,000 cells per well.    -   IPC298: 2,000 cells per well.

On day 2, compound at a maximum concentration of 5 mM is seriallydiluted 1:3 (e.g. 10 μL with 30 μL dimethyl sulfoxide) for a total of 8point titration with DMSO as a control. A 1 μL aliquot of each dilutionpoint and control is added to 249 μL growth media and 50 μL is added toa well containing cells, providing 10 μM compound at the maximumconcentration point. The cells are incubated for 3 days at 37° C. in 5%CO₂.

On day 5, ATPlite 1 step Luminescence Assay System (Perkin Elmer#6016739) is brought to room temperature along with the cell cultures.ATPlite is added 25 μL to each well, shake for 2 minutes, and the cellsare incubated at room temperature for 10 minutes, then luminescence isread on Safire reader. The measured luminescence correlates directlywith cell number, such that the reading as a function of compoundconcentration is used to determine the IC₅₀ value.

B9 is a squamous cell carcinoma cell line expressing activated HRAS thatwas isolated from a DMBA/TPA-induced mouse model of skin carcinogenesis(Stoler, et al. The Journal of Cell Biology, 1993, 122(5), 1103-17).IPC-298 is a human melanoma cell line that expresses activated NRAS(Aubert, et al. International Journal of Cancer, 1993, 54(5), 784-92).To determine whether compounds induce phosphorylated ERK and MEK, cellsare plated in a 96-well dish and treated with an 8-point titration ofcompound for one hour at 37° C. The media is then removed and the cellsare incubated with lysis buffer containing protease and phosphataseinhibitors. Phosphorylated ERK and MEK in the resulting lysates isdetected using AlphaScreen™ technology. To detect phosphorylated ERK,cell lysates are incubated with streptavidin-coated donor beads,anti-mouse IgG acceptor beads, a biotinylated anti-ERK1/2 rabbitantibody, and a mouse antibody that recognizes ERK1/2 only when it isphosphorylated on Thr202 and Tyr204. The biotinylated ERK1/2 antibodywill bind to both the streptavidin-coated donor beads and to ERK1/2(regardless of its phosphorylation state), and the phospho-ERK1/2antibody will bind to the acceptor beads and to ERK1/2 that isphosphorylated at Thr202/Tyr204. Excitation of the beads with laserlight at 680 nm produces singlet oxygen, which is rapidly quenchedunless the beads are in close proximity. When ERK is phosphorylated,both antibodies can bind the same protein, bringing the donor andacceptor beads into close proximity, producing a signal that can bemeasured at 580 nm. MEK phosphorylation is detected using a similarapproach, only with antibodies directed against total MEK1/2 and MEK1/2that is phosphorylated at Ser217 and Ser221.

It is understood that the results of these assays may vary as assayconditions are varied. Inhibition levels determined under the conditionsdescribed herein represent a relative activity for the compounds testedunder the specific conditions employed. The cell based assays are likelyto show variability due to the complexity of the system and thesensitivity thereof to any changes in the assay conditions. As such,some level of inhibition in the cell based assays is indicative of thecompounds having some inhibitory activity for those cells, whereas lackof inhibition below the threshold of the highest concentration testeddoes not necessarily indicate that the compound has no inhibitoryactivity on the cells, only that under the conditions tested, noinhibition is observed. In some instances, the compounds were not testedin all of the assays, or assay results were not valid, as indicated byNA in the tables below.

The following table provides data indicating the B-Raf V600E andIPC-298_P-ERK cell activation activity, A375_P-ERK and COLO205 cellgrowth inhibitory activity for exemplary compounds as described herein:

Biochemical Cell activity activity Compound (IC₅₀ μM) (EC₅₀ μM) Cellactivity (IC₅₀ μM) number V600E IPC-298_P-ERK A375 COLO205 P-0012<0.1 >10 <1 >1 P-0013 <0.1 >10 <1 >1 P-0014 <0.1 >8 <1 <1 P-0015<0.1 >10 <1 >1 P-0016 <0.1 NA <1 <1 P-0017 <0.1 >10 <1 >1 P-0018<0.1 >10 <1 >1 P-0019 <0.1 >10 <1 >1 P-0020 <0.1 >10 <1 <1 P-0021<0.1 >10 <1 <1 P-0022 <0.1 >10 <1 <1 P-0023 <0.1 >10 <1 >1 P-0024<0.1 >10 <1 >1 P-0025 <0.1 >10 <1 <1 P-0026 >0.1 >10 >1 P-0027 <0.1 NA<1 <1 P-0028 <0.1 >10 <1 <1 P-0029 <0.1 >10 <1 <1 P-0030 <0.1 >10 <1 <1P-0031 <0.1 >10 <1 <1 P-0032 <0.1 >10 <1 <1 P-0033 <0.1 >10 <1 <1 P-0034<0.1 >10 <1 >1 P-0035 <0.1 >10 <1 >1 P-0036 <0.1 >10 <1 >1 P-0037<0.1 >10 <1 >1 P-0038 <0.1 >10 <1 >1 P-0039 <0.1 >10 <1 >1 P-0040<0.1 >10 <1 <1 P-0041 >0.1 >10 >1 P-0042 <0.1 >10 <1 <1 P-0043 <0.1 >10<1 <1 P-0044 <0.1 >10 <1 <1 P-0045 <0.1 >10 <1 <1 P-0046 <0.1 >10 <1 <1P-0047 <0.1 >10 <1 <1 P-0048 <0.1 >10 <1 P-0049 <0.1 >4 <1 <1 P-0050<0.1 >10 <1 <1 P-0051 <0.1 >10 <1 <1 P-0052 <0.1 >10 <1 <1 P-0053<0.1 >10 <1 <1 P-0054 <0.1 >1 <1 >1 P-0055 <0.1 >10 <1 <1 P-0056<0.1 >10 <1 <1 P-0057 <0.1 >10 <1 <1 P-0058 <0.1 >10 <1 <1 P-0059<0.1 >10 <1 <1 P-0060 <0.1 >2 <1 <1 P-0061 <0.1 >10 <1 <1 P-0062<0.1 >10 <1 <1 P-0063 <0.1 >10 <1 <1 P-0064 <0.1 >10 <1 <1 P-0065 <0.1<1 >1 P-0066 <0.1 <1 <1 P-0067 <0.1 <1 >1 P-0068 <0.1 P-0069 <0.1P-0070 >0.1 <1 >1 P-0071 >0.1 <1 >1 P-0072 >0.1 <1 >1 P-0073 >0.1 <1 >1P-0074 >0.1 <1 >1 P-0075 >0.1 <1 >1 P-0076 <0.1 <1 <1 P-0077 <0.1 <1 <1P-0078 <0.1 <1 >1 P-0079 <0.1 <1 <1 P-0080 <0.1 <1 >1 P-0081 <0.1 <1 <1P-0082 <0.1 <1 <1 P-0083 <0.1 <1 <1 P-0084 <0.1 <1 <1 P-0085 <0.1 <1 >1P-0086 <0.1 <1 <1 P-0087 <0.1 <1 <1 P-0088 <0.1 <1 >1 P-0089 <0.1 <1 >1P-0090 <0.1 <1 <1 P-0091 <0.1 <1 <1 P-0092 <0.1 <1 <1 P-0093 <0.1 <1 <1P-0094 <0.1 <1 <1 P-0095 <0.1 <1 <1 P-0096 <0.1 <1 <1 P-0097 <0.1 <1 <1P-0098 <0.1 <1 <1 P-0099 <0.1 <1 >1 P-0100 <0.1 <1 >1 P-0101 <0.1 <1 >1P-0102 <0.1 <1 >1 P-0103 <0.1 <1 <1 P-0104 <0.1 <1 <1 P-0105 <0.1 <1 <1P-0106 <0.1 <1 <1 P-0107 <0.1 <1 <1 P-0108 <0.1 <1 >1 P-0109 <0.1 <1 <1P-0235 <0.1 <1 <1 P-0236 <0.1 <1 <1 P-0237 <0.1 <1 <1 P-0238 <0.1 <1 <1P-0239 <0.1 <1 <1 P-0240 <0.1 <1 <1 P-0241 <0.1 <1 <1 P-0242 <0.1 >1 >1P-0243 <0.1 >1 >1 P-0244 <0.1 >1 >1 P-0245 <0.1 <1 <1 P-0246 <0.1 >1 >1P-0247 <0.1 <1 <1 P-0248 <0.1 <1 <1 P-0249 <0.1 <1 <1 P-0251 <0.1 >1 >1P-0252 <0.1 <1 <1 P-0253 <0.1 >1 >1 P-0254 <0.1 <1 <1 P-0255 <0.1 <1 <1P-0256 <0.1 <1 <1 P-0257 >0.1 >1 P-0258 <0.1 <1 <1 P-0259 <0.1 <1 <1P-0260 <0.1 <1 <1 P-0261 <0.1 <1 <1 P-0262 <0.1 <1 <1 P-0263 <0.1 <1 <1P-0264 <0.1 <1 <1 P-0265 <0.1 >2 <1 <1 P-0266 <0.1 <1 <1 P-0267 >0.1P-0268 <0.1 <1 <1 P-0269 <0.1 <1 <1 P-0270 <0.1 <1 <1 P-0271 <0.1 <1 <1P-0272 >0.1 P-0273 <1 <1 P-0274 <0.1 <1 >1 P-0275 <0.1 <1 <1 P-0276 <0.1<1 >1 P-0277 >0.1 <1 <1 P-0279 <0.1 >1 <1 P-0280 <1 <1 P-0281 <0.1 <1 <1P-0282 <0.1 <1 <1 P-0283 <0.1 >1 <1 P-0284 <1 <1 P-0285 <0.1 <1 <1P-0286 <0.1 >1 <1 P-0287 >4 <1 <1 P-0288 <0.1 >2 <1 <1 P-0289 <0.1 <1 <1P-0291 >0.1 P-0292 <1 <1 P-0293 <0.1 <1 <1 P-0294 <0.1 >1 >1 P-0295<0.1 >2 <1 <1 P-0297 <0.1 >1 >1 P-0298 <0.1 >1 >1 P-0299 <0.1 >1 >1P-0300 <0.1 >4 <1 >1 P-0301 <0.1 <1 >1 P-0302 <0.1 <1 <1 P-0303<0.1 >1 >1 P-0304 <0.1 <1 <1 P-0305 <0.1 <1 <1 P-0306 <0.1 >1 <1 P-0307<0.1 <1 <1 P-0308 <0.1 <1 <1 P-0309 <0.1 <1 <1 P-0310 <0.1 <1 <1 P-0311<0.1 <1 <1 P-0312 <0.1 <1 <1 P-0313 <0.1 <1 <1 P-0314 <0.1 <1 <1 P-0315<0.1 <1 <1 P-0316 <0.1 <1 <1 P-0317 <0.1 <1 <1 P-0318 <0.1 <1 <1 P-0319<0.1 <1 <1 P-0320 >0.1 P-0321 <0.1 <1 <1 P-0322 <0.1 <1 <1 P-0324 <0.1<1 <1 P-0325 <0.1 <1 >1 P-0326 <0.1 >1 >1 P-0327 <0.1 <1 <1 P-0334<0.1 >2 >1 >1 P-0335 <0.1 <1 <1 P-0336 >0.1 >4 P-0337 <0.1 >1 >1 P-0338<0.1 <1 <1 P-0339 <0.1 <1 <1 P-0340 <0.1 <1 <1 P-0223 >0.1 P-0224 <0.1<1 <1 P-0225 <0.1 <1 <1 P-0226 <0.1 <1 <1 P-0227 <0.1 <1 <1 P-0228 <0.1<1 <1 P-0229 <0.1 <1 <1 P-0230 <0.1 <1 <1 P-0231 <0.1 <1 <1 P-0232 <0.1<1 <1 P-0233 <0.1 >1 >1 P-0117 >0.1 >1 >1 P-0116 <0.1 <1 <1 P-0115 <0.1<1 <1 P-0114 <0.1 <1 <1 P-0113 <0.1 <1 <1 P-0112 <0.1 <1 <1 P-0111 <0.1<1 <1 P-0110 <0.1 <1 <1

The table below provides the IPC-298_P-ERK cell activation activity,A375_P-ERK and COLO205 cell growth inhibitory activity data for a fewexemplary compounds known in the art.

Cell activity Cell activity (EC₅₀ μM) (IC₅₀ μM) Compound IPC-298_P-ERKA375 COLO205 N-[3-(5-chloro-1H-pyrrolo[2,3- <0.5 <0.8 <1b]pyridine-3-carbonyl)-2,4- difluoro-phenyl]propane-1- sulfonamideN-[2,4-difluoro-3-[5-(2-methoxy- <0.5 <0.5 <1pyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl]phenyl]-2-fluoro-benzenesulfonamide N-[2,4-difluoro-3-[5-(2-methoxy- <1 <0.5 <1pyrimidin-5-yl)-1H-pyrrolo[2,3- b]pyridine-3-carbonyl]phenyl]-2,5-difluoro-benzenesulfonamide

Pharmacokinetic properties of compounds (including any solid forms orformulations thereof) are assessed in male Sprague Dawley rats or maleBeagle dogs. Rats are dosed daily with compound either by IV injectionsvia surgically implanted jugular catheters or by oral gavage (PO). Eachcompound is prepared as a 20 mg/mL stock solution in dimethyl sulfoxide,which is further diluted to provide the dosing stock at the desiredconcentration for the IV or PO formulations. For IV dosing, the dosingstock is diluted into a 1:1:8 mixture of Solutol R:ethanol:water. For POdosing, the dosing stock is diluted into 1% methylcellulose. In acassette format (or each compound, solid form thereof or formulationthereof is done individually), compounds are diluted to 0.5 mg/mL eachfor IV dosing and 0.4 mg/mL each for PO dosing and dosed at 1 mg/kg (2mL/kg) or 2 mg/kg (5 mL/kg), respectively. For IV dosed animals, tailvein blood samples are collected with lithium heparin anticoagulant at5, 15, 30, and 60 minutes and 4, 8, and 24 hours post dosing each day.For PO dosed animals, tail vein blood samples are collected with lithiumheparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosingeach day. Dogs are dosed daily by oral capsules in a suitableformulation at 50 mg/mL. Cephalic vein blood samples are collected withlithium heparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hourspost dosing each day. All samples are processed to plasma and frozen forlater analysis of each compound by LC/MS/MS. Plasma levels as a functionof time are plotted to assess the AUC (ng*hr/mL). Compounds according tothe present invention preferably show improved pharmacokineticproperties relative to previously described compounds, i.e. they havesubstantially higher values for one or more of AUC, Cmax and half-liferelative to previously described compounds.

All patents, patent applications and other references cited in thespecification are indicative of the level of skill of those skilled inthe art to which the invention pertains, and are incorporated byreference in their entireties, including any tables and figures, to thesame extent as if each reference had been incorporated by reference inits entirety individually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any two different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

1.-55. (canceled)
 56. A method for treating a subject with a B-Rafmediated disease or condition, said method comprising administering tosaid subject an effective amount of a compound of having formula (Ig-1):

or a pharmaceutically acceptable salt or isomer thereof, wherein: Z is

 or —N(CH₃)(CH₂CH₃); R¹⁵ is cyclopropyl; R¹¹ is halogen; Q is H or F; Y²is H; n is 2; and m is 0, 1 or
 2. 57. The method of claim 56, wherein Zis —N(CH₃)(CH₂CH₃).
 58. The method of claim 56, wherein the compound isof formula (Ig-2):

or a pharmaceutically acceptable salt or isomer thereof.
 59. The methodof claim 58, wherein R¹¹ is fluoro.
 60. The method of claim 58, whereinQ is H.
 61. The method of claim 58, wherein Q is F.
 62. The method ofclaim 58, wherein m is
 0. 63. The method of claim 58, wherein m is 1.64. The method of claim 58, wherein the compound is the followingstructure:

or a pharmaceutically acceptable salt thereof.
 65. The method of claim64, wherein the B-Raf mediated disease or condition is ischemic stroke,cerebrovascular ischemia, multi-infarct dementia, head injury, spinalcord injury, Alzheimer's disease, Parkinson's disease, amyotrophiclateral sclerosis, dementia, senile chorea, Huntington's disease,neoplastic disease, complications with neoplastic disease,chemotherapy-induced hypoxia, gastrointestinal stromal tumors, prostatetumors, mast cell tumors, canine mast cell tumors, acute myeloidleukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chroniclymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, glioma,glioblastoma, astrocytoma, neuroblastoma, sarcomas, sarcomas ofneuroectodermal origin, leiomyosarcoma, lung carcinoma, breastcarcinoma, pancreatic carcinoma, colon carcinoma, hepatocellularcarcinoma, renal carcinoma, carcinoma of the female genital tract,squamous cell carcinoma, carcinoma in situ, lymphoma, histiocyticlymphoma, non-Hodgkin's lymphoma, MEN2 syndromes, neurofibromatosis,Schwann cell neoplasia, myelodysplastic syndrome, leukemia, tumorangiogenesis, thyroid cancer, liver cancer, bone cancer, skin cancer,brain cancer, cancer of the central nervous system, pancreatic cancer,lung cancer, small cell lung cancer, non small cell lung cancer, breastcancer, colon cancer, bladder cancer, prostate cancer, gastrointestinaltract cancer, cancer of the endometrium, fallopian tubecancer,testicular cancer, ovarian cancer, pain of neuropathic origin, pain ofinflammatory origin, acute pain, chronic pain, migraine, cardiovasculardisease, heart failure, cardiac hypertrophy, thrombosis, thromboticmicroangiopathy syndromes, atherosclerosis, reperfusion injury,ischemia, cerebrovascular ischemia, liver ischemia, inflammation,polycystic kidney disease, age-related macular degeneration, rheumatoidarthritis, allergic rhinitis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, systemic lupus erythematosis, Sjogren'sSyndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronicthyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis,osteoarthritis, endometriosis, dermal scarring, tissue scarring,vascular restenosis, fibrotic disorders, hypereosinophilia, CNSinflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis,immunodeficiency diseases, severe combined immunodeficiency, organtransplant rejection, graft versus host disease, renal disease,prostatic disease, diabetic nephropathy, nephrosclerosis,glomerulonephritis, interstitial nephritis, Lupus nephritis, prostatehyperplasia, chronic renal failure, tubular necrosis,diabetes-associated renal complication, associated renal hypertrophy,type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepaticsteatosis, insulin resistance, hyperglycemia, lipolysis obesity,infection, Helicobacter pylori infection, Influenza virus infection,fever, sepsis, pulmonary diseases, chronic obstructive pulmonarydisease, acute respiratory distress syndrome, asthma, allergy,bronchitis, emphysema, pulmonary fibrosis, genetic developmentaldiseases, Noonan's syndrome, Crouzon syndrome, acrocephalo-syndactylytype I, Pfeiffer's syndrome, Jackson-Weiss syndrome, Costello syndrome,faciocutaneoskeletal syndrome, leopard syndrome, cardio-faciocutaneoussyndrome, neural crest syndrome abnormalities causing cardiovascular,skeletal, intestinal, skin, hair or endocrine diseases, disorders ofbone structure or mineralization, osteoporosis, increased risk offracture, hypercalcemia, bone metastases, Grave's disease,Hirschsprung's disease, lymphoedema, selective T-cell defect, X-linkedagammaglobulinemia, diabetic retinopathy, alopecia, erectiledysfunction, or tuberous sclerosis.
 66. The method of claim 65, whereinsaid disease or condition is B-Raf V600E melanoma.
 67. The method ofclaim 65, wherein said disease or condition B-Raf V600E non-small celllung cancer.
 68. The method of claim 65, wherein said disease orcondition is B-Raf V600E colon cancer.